95 results on '"Alison C. Holloway"'
Search Results
2. Naphthenic acid fraction components from oil sands process-affected water from the Athabasca Oil Sands Region impair murine osteoblast differentiation and function
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Robert M. Gutgesell, Laiba Jamshed, Richard A. Frank, L. Mark Hewitt, Philippe J. Thomas, and Alison C. Holloway
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Mice ,Osteoblasts ,Osteogenesis ,Carboxylic Acids ,Animals ,Water ,Oil and Gas Fields ,Toxicology ,Water Pollutants, Chemical - Abstract
The extraction of bitumen from surface mining in the Athabasca Oil Sands Region (AOSR) produces large quantities of oil sands process-affected water (OSPW) that needs to be stored in settling basins near extraction sites. Chemical constituents of OSPW are known to impair bone health in some organisms, which can lead to increased fracture risk and lower reproductive fitness. Naphthenic acid fraction components (NAFCs) are thought to be among the most toxic class of compounds in OSPW; however, the effect of NAFCs on osteoblast development is largely unknown. In this study, we demonstrate that NAFCs from OSPW inhibit osteoblast differentiation and deposition of extracellular matrix, which is required for bone formation. Extracellular matrix deposition was inhibited in osteoblasts exposed to 12.5-125 mg/L of NAFC for 21 days. We also show that components within NAFCs inhibit the expression of gene markers of osteoblast differentiation and function, namely, alkaline phosphatase (Alp), osteocalcin, and collagen type 1 alpha 1 (Col1a1). These effects were partially mediated by the induction of glucocorticoid receptor (GR) activity; NAFC induces the expression of the GR activity marker genes Sgk1 (12.5 mg/L) and p85a (125 mg/L) and inhibits GR protein (125 mg/L) and Opg RNA (12.5 mg/L) expression. This study provides evidence that NAFC concentrations of 12.5 mg/L and above can directly act on osteoblasts to inhibit bone formation and suggests that NAFCs contain components that can act as GR agonists, which may have further endocrine disrupting effects on exposed wildlife.
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- 2022
3. Prenatal Exposure to Delta-9-tetrahydrocannabinol (THC) Alters the Expression of miR-122-5p and Its Target
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Annia A, Martínez-Peña, Kendrick, Lee, Madison, Pereira, Ahmed, Ayyash, James J, Petrik, Daniel B, Hardy, and Alison C, Holloway
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MicroRNAs ,Pregnancy ,Prenatal Exposure Delayed Effects ,Ovary ,Hallucinogens ,Animals ,Humans ,Female ,Dronabinol ,Rats ,Receptor, IGF Type 1 - Abstract
As cannabis use during pregnancy increases, it is important to understand its effects on the developing fetus. Particularly, the long-term effects of its psychoactive component, delta-9-tetrahydrocannabinol (THC), on the offspring's reproductive health are not fully understood. This study examined the impact of gestational THC exposure on the miRNA profile in adult rat ovaries and the possible consequences on ovarian health. Prenatal THC exposure resulted in the differential expression of 12 out of 420 evaluated miRNAs. From the differentially expressed miRNAs, miR-122-5p, which is highly conserved among species, was the only upregulated target and had the greatest fold change. The upregulation of miR-122-5p and the downregulation of its target insulin-like growth factor 1 receptor (
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- 2022
4. Increased gut serotonin production in response to bisphenol A structural analogs may contribute to their obesogenic effects
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Nicole G. Barra, Yun Han Kwon, Katherine M. Morrison, Gregory R. Steinberg, Michael G. Wade, Waliul I Khan, Mathilakath M. Vijayan, Jonathan D. Schertzer, and Alison C. Holloway
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Serotonin ,Phenols ,Physiology ,Physiology (medical) ,Endocrinology, Diabetes and Metabolism ,Animals ,Obesity ,Benzhydryl Compounds ,Endocrine Disruptors - Abstract
Obesogens are synthetic, environmental chemicals that can disrupt endocrine control of metabolism and contribute to the risk of obesity and metabolic disease. Bisphenol A (BPA) is one of the most studied obesogens. There is considerable evidence that BPA exposure is associated with weight gain, increased adiposity, poor blood glucose control, and nonalcoholic fatty liver disease in animal models and human populations. Increased usage of structural analogs of BPA has occurred in response to legislation banning their use in some commercial products. However, BPA analogs may also cause some of the same metabolic impairments because of common mechanisms of action. One key effector that is altered by BPA and its analogs is serotonin, however, it is unknown if BPA-induced changes in peripheral serotonin pathways underlie metabolic perturbations seen with BPA exposure. Upon ingestion, BPA and its analogs act as endocrine-disrupting chemicals in the gastrointestinal tract to influence serotonin production by the gut, where over 95% of serotonin is produced. The purpose of this review is to evaluate how BPA and its analogs alter gut serotonin regulation and then discuss how disruption of serotonergic networks influences host metabolism. We also provide evidence that BPA and its analogs enhance serotonin production in gut enterochromaffin cells. Taken together, we propose that BPA and many BPA analogs represent endocrine-disrupting chemicals that can influence host metabolism through the endogenous production of gut-derived factors, such as serotonin.
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- 2022
5. An Emerging Cross-Species Marker for Organismal Health: Tryptophan-Kynurenine Pathway
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Laiba Jamshed, Amrita Debnath, Shanza Jamshed, Jade V. Wish, Jason C. Raine, Gregg T. Tomy, Philippe J. Thomas, and Alison C. Holloway
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Inflammation ,Mammals ,Organic Chemistry ,Tryptophan ,General Medicine ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,Animals ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Biomarkers ,Ecosystem ,Kynurenine - Abstract
Tryptophan (TRP) is an essential dietary amino acid that, unless otherwise committed to protein synthesis, undergoes metabolism via the Tryptophan-Kynurenine (TRP-KYN) pathway in vertebrate organisms. TRP and its metabolites have key roles in diverse physiological processes including cell growth and maintenance, immunity, disease states and the coordination of adaptive responses to environmental and dietary cues. Changes in TRP metabolism can alter the availability of TRP for protein and serotonin biosynthesis as well as alter levels of the immune-active KYN pathway metabolites. There is now considerable evidence which has shown that the TRP-KYN pathway can be influenced by various stressors including glucocorticoids (marker of chronic stress), infection, inflammation and oxidative stress, and environmental toxicants. While there is little known regarding the role of TRP metabolism following exposure to environmental contaminants, there is evidence of linkages between chemically induced metabolic perturbations and altered TRP enzymes and KYN metabolites. Moreover, the TRP-KYN pathway is conserved across vertebrate species and can be influenced by exposure to xenobiotics, therefore, understanding how this pathway is regulated may have broader implications for environmental and wildlife toxicology. The goal of this narrative review is to (1) identify key pathways affecting Trp-Kyn metabolism in vertebrates and (2) highlight consequences of altered tryptophan metabolism in mammals, birds, amphibians, and fish. We discuss current literature available across species, highlight gaps in the current state of knowledge, and further postulate that the kynurenine to tryptophan ratio can be used as a novel biomarker for assessing organismal and, more broadly, ecosystem health.
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- 2022
6. Early Life Exposure to Nicotine: Postnatal Metabolic, Neurobehavioral and Respiratory Outcomes and the Development of Childhood Cancers
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Alison C. Holloway, Shanza Jamshed, Laiba Jamshed, and Genevieve A. Perono
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Nicotine ,Offspring ,medicine.medical_treatment ,Physiology ,Electronic Nicotine Delivery Systems ,Toxicology ,03 medical and health sciences ,0302 clinical medicine ,Pharmacotherapy ,Pregnancy ,Neoplasms ,Contemporary Review ,medicine ,Animals ,Humans ,030212 general & internal medicine ,Child ,business.industry ,Infant, Newborn ,Neurotoxicity ,Nicotine replacement therapy ,medicine.disease ,Tobacco Use Cessation Devices ,3. Good health ,Prenatal Exposure Delayed Effects ,Smoking cessation ,Female ,Smoking Cessation ,Animal studies ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Cigarette smoking during pregnancy is associated with numerous obstetrical, fetal, and developmental complications, as well as an increased risk of adverse health consequences in the adult offspring. Nicotine replacement therapy and electronic nicotine delivery systems (e-cigarettes) have been developed as a pharmacotherapy for smoking cessation and are considered safer alternatives for women to smoke during pregnancy. The safety of nicotine replacement therapy use during pregnancy has been evaluated in a limited number of short-term human trials, but there is currently no information on the long-term effects of developmental nicotine exposure in humans. However, animal studies suggest that nicotine alone may be a key chemical responsible for many of the long-term effects associated with maternal cigarette smoking on the offspring and increases the risk of adverse neurobehavioral outcomes, dysmetabolism, respiratory illness, and cancer. This review will examine the long-term effects of fetal and neonatal nicotine exposure on postnatal health.
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- 2020
7. Impact of pesticide exposure on adipose tissue development and function
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Gregory R. Steinberg, Alison C. Holloway, Robert M Gutgesell, Evangelia E. Tsakiridis, and Shanza Jamshed
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Adipose tissue ,Physiology ,Type 2 diabetes ,White adipose tissue ,010501 environmental sciences ,01 natural sciences ,Biochemistry ,Body Mass Index ,03 medical and health sciences ,Metabolic Diseases ,Diabetes mellitus ,Brown adipose tissue ,medicine ,Animals ,Humans ,Obesity ,Pesticides ,Molecular Biology ,030304 developmental biology ,0105 earth and related environmental sciences ,0303 health sciences ,Adipogenesis ,business.industry ,Environmental Exposure ,Cell Biology ,Environmental exposure ,medicine.disease ,medicine.anatomical_structure ,Adipose Tissue ,business - Abstract
Obesity is a leading cause of morbidity, mortality and health care expenditure whose incidence is rapidly rising across the globe. Although the cause of the obesity epidemic is typically viewed as a product of an increased availability of high calorie foods and/or a reduction in physical activity, there is mounting evidence that exposure to synthetic chemicals in our environment may play an important role. Pesticides, are a class of chemicals whose widespread use has coincided with the global rise of obesity over the past two decades. Importantly, given their lipophilic nature many pesticides have been shown to accumulate with adipose tissue depots, suggesting they may be disrupting the function of white adipose tissue (WAT), brown adipose tissue (BAT) and beige adipose tissue to promote obesity and metabolic diseases such as type 2 diabetes. In this review, we discuss epidemiological evidence linking pesticide exposure with body mass index (BMI) and the incidence of diabetes. We then review preclinical studies in rodent models which have directly evaluated the effects of different classes of insecticides and herbicides on obesity and metabolic dysfunction. Lastly, we review studies conducted in adipose tissue cells lines and the purported mechanisms by which pesticides may induce alterations in adipose tissue function. The review of the literature reveals major gaps in our knowledge regarding human exposure to pesticides and our understanding of whether physiologically relevant concentrations promote obesity and elicit alterations in key signaling pathways vital for maintaining adipose tissue metabolism.
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- 2020
8. Chronic exposure to synthetic food colorant Allura Red AC promotes susceptibility to experimental colitis via intestinal serotonin in mice
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Yun Han Kwon, Suhrid Banskota, Huaqing Wang, Laura Rossi, Jensine A. Grondin, Saad A. Syed, Yeganeh Yousefi, Jonathan D. Schertzer, Katherine M. Morrison, Michael G. Wade, Alison C. Holloway, Michael G. Surette, Gregory R. Steinberg, and Waliul I. Khan
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Serotonin ,Multidisciplinary ,Colon ,Dextran Sulfate ,General Physics and Astronomy ,Food Coloring Agents ,General Chemistry ,Colitis ,General Biochemistry, Genetics and Molecular Biology ,Intestines ,Mice, Inbred C57BL ,Mice ,Humans ,Animals ,Intestinal Mucosa - Abstract
Chemicals in food are widely used leading to significant human exposure. Allura Red AC (AR) is a highly common synthetic colorant; however, little is known about its impact on colitis. Here, we show chronic exposure of AR at a dose found in commonly consumed dietary products exacerbates experimental models of colitis in mice. While intermittent exposure is more akin to a typical human exposure, intermittent exposure to AR in mice for 12 weeks, does not influence susceptibility to colitis. However, exposure to AR during early life primes mice to heightened susceptibility to colitis. In addition, chronic exposure to AR induces mild colitis, which is associated with elevated colonic serotonin (5-hydroxytryptamine; 5-HT) levels and impairment of the epithelial barrier function via myosin light chain kinase (MLCK). Importantly, chronic exposure to AR does not influence colitis susceptibility in mice lacking tryptophan hydroxylase 1 (TPH1), the rate limiting enzyme for 5-HT biosynthesis. Cecal transfer of the perturbed gut microbiota by AR exposure worsens colitis severity in the recipient germ-free (GF) mice. Furthermore, chronic AR exposure elevates colonic 5-HT levels in naïve GF mice. Though it remains unknown whether AR has similar effects in humans, our study reveals that chronic long-term exposure to a common synthetic colorant promotes experimental colitis via colonic 5-HT in gut microbiota-dependent and -independent pathway in mice.
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- 2021
9. Low brown adipose tissue activity linked to NAFLD
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Eric M. Desjardins, Nicole G. Barra, Stephan Oreskovich, Julian M. Yabut, Elizabeth Gunn, Denis P. Blondin, Fernando F. Anhê, Gregory R. Steinberg, Alison C. Holloway, Zubin Punthakee, Katherine M. Morrison, Jonathan D. Schertzer, Basma A. Ahmed, Michael G. Surette, Frank J. Ong, Jake C. Szamosi, Nina P. Singh, Emily K. Hutchings, Saad A. Syed, André C. Carpentier, Norman B. Konyer, Kevin P. Foley, Michael D. Noseworthy, and François Haman
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Male ,Medicine (General) ,Pathology ,Endocrinology, Diabetes and Metabolism ,adult humans ,cold exposure ,Physiology ,Disease ,Gut flora ,Endocrinology ,Adipose Tissue, Brown ,Brown adipose tissue ,Homeostasis ,magnetic resonance imaging ,Adiposity ,proton density fat fraction ,Fatty liver ,Middle Aged ,Cold Temperature ,medicine.anatomical_structure ,Female ,Adult ,medicine.medical_specialty ,animal structures ,Adolescent ,MEDLINE ,Biology ,digestive system ,General Biochemistry, Genetics and Molecular Biology ,Article ,fecal transplant ,Young Adult ,R5-920 ,Liver steatosis ,germ-free mice ,medicine ,microbiota ,Animals ,Humans ,Feces ,business.industry ,non-alcoholic fatty liver disease ,Non alcoholic ,brown adipose tissue ,Fecal bacteriotherapy ,biology.organism_classification ,medicine.disease ,hepatic fat ,Gastrointestinal Microbiome ,Mice, Inbred C57BL ,Multivariate Analysis ,business - Abstract
Summary In rodents, lower brown adipose tissue (BAT) activity is associated with greater liver steatosis and changes in the gut microbiome. However, little is known about these relationships in humans. In adults (n = 60), we assessed hepatic fat and cold-stimulated BAT activity using magnetic resonance imaging and the gut microbiota with 16S sequencing. We transplanted gnotobiotic mice with feces from humans to assess the transferability of BAT activity through the microbiota. Individuals with NAFLD (n = 29) have lower BAT activity than those without, and BAT activity is inversely related to hepatic fat content. BAT activity is not related to the characteristics of the fecal microbiota and is not transmissible through fecal transplantation to mice. Thus, low BAT activity is associated with higher hepatic fat accumulation in human adults, but this does not appear to have been mediated through the gut microbiota., Graphical abstract, Highlights Adults with NAFLD have lower brown adipose tissue activity compared with controls Brown adipose tissue (BAT) activity is not linked to fecal gut microbiota BAT activity is not transmissible to mice via fecal transplantation, Ahmed et al. show, using MRI, that higher cold-stimulated BAT activity is linked to lower hepatic fat in 60 adults. BAT activity is not linked to fecal gut microbiota characteristics and is not transmissible to germ-free mice. Gut microbiota does not link BAT activity and liver fat.
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- 2021
10. The pesticide chlorpyrifos promotes obesity by inhibiting diet-induced thermogenesis in brown adipose tissue
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James S. V. Lally, Gregory R. Steinberg, Andrew G. McArthur, Evangelia E. Tsakiridis, Brennan K. Smith, Michael G. Wade, Katherine M. Morrison, Julian M. Yabut, Bo Wang, Shuman Zhang, Krishna A Srinivasan, Jagdish Suresh Patel, Alison C. Holloway, Shingo Kajimura, Eric M. Desjardins, Amogelang R. Raphenya, Emily A. Day, Alex E. Green, Andrea Llanos, and Jianhan Wu
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Male ,medicine.medical_specialty ,Science ,General Physics and Astronomy ,030209 endocrinology & metabolism ,Food Contamination ,Biology ,Diet induced thermogenesis ,p38 Mitogen-Activated Protein Kinases ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Insulin resistance ,AMP-Activated Protein Kinase Kinases ,Adipose Tissue, Brown ,Internal medicine ,Mitophagy ,Brown adipose tissue ,medicine ,Cyclic AMP ,Animals ,Humans ,Obesity ,Pesticides ,Uncoupling Protein 1 ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Organophosphate ,AMPK ,Thermogenesis ,General Chemistry ,medicine.disease ,Thermogenin ,Mice, Inbred C57BL ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Chlorpyrifos ,Energy Metabolism ,Protein Kinases - Abstract
Obesity results from a caloric imbalance between energy intake, absorption and expenditure. In both rodents and humans, diet-induced thermogenesis contributes to energy expenditure and involves the activation of brown adipose tissue (BAT). We hypothesize that environmental toxicants commonly used as food additives or pesticides might reduce BAT thermogenesis through suppression of uncoupling protein 1 (UCP1) and this may contribute to the development of obesity. Using a step-wise screening approach, we discover that the organophosphate insecticide chlorpyrifos suppresses UCP1 and mitochondrial respiration in BAT at concentrations as low as 1 pM. In mice housed at thermoneutrality and fed a high-fat diet, chlorpyrifos impairs BAT mitochondrial function and diet-induced thermogenesis, promoting greater obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance. This is associated with reductions in cAMP; activation of p38MAPK and AMPK; protein kinases critical for maintaining UCP1 and mitophagy, respectively in BAT. These data indicate that the commonly used pesticide chlorpyrifos, suppresses diet-induced thermogenesis and the activation of BAT, suggesting its use may contribute to the obesity epidemic., Chlorpyrifos is a widely-used pesticide and a common residue on vegetables and fruits. Here the authors show that at non-neurotoxic doses, chlorpyrifos reduces energy expenditure, by inhibiting diet induced thermogenesis, and promotes obesity and insulin resistance.
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- 2021
11. The Impact of Early Life Exposure to Cannabis: The Role of the Endocannabinoid System
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O’Llenecia S. Walker, Harmeet Gurm, Alison C. Holloway, Annia A. Martínez-Peña, Sandeep Raha, Genevieve A. Perono, Reeti Sharma, Shamini Selvakumar, and Sarah Alexis Gritis
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cannabis ,Marijuana Abuse ,medicine.medical_treatment ,fetal development ,Review ,Bioinformatics ,0302 clinical medicine ,Δ9-THC ,endocannabinoid system ,Biology (General) ,Spectroscopy ,0303 health sciences ,biology ,General Medicine ,Endocannabinoid system ,3. Good health ,Computer Science Applications ,Chemistry ,Maternal Exposure ,Prenatal Exposure Delayed Effects ,Female ,pregnancy ,placenta ,Offspring ,QH301-705.5 ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,Intensive care ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,reproductive health ,Molecular Biology ,QD1-999 ,Effects of cannabis ,030304 developmental biology ,Fetus ,Pregnancy ,business.industry ,Organic Chemistry ,medicine.disease ,biology.organism_classification ,Cannabis ,Cannabinoid ,business ,030217 neurology & neurosurgery ,Endocannabinoids - Abstract
Cannabis use during pregnancy has continued to rise, particularly in developed countries, as a result of the trend towards legalization and lack of consistent, evidence-based knowledge on the matter. While there is conflicting data regarding whether cannabis use during pregnancy leads to adverse outcomes such as stillbirth, preterm birth, low birthweight, or increased admission to neonatal intensive care units, investigations into long-term effects on the offspring’s health are limited. Historically, studies have focused on the neurobehavioral effects of prenatal cannabis exposure on the offspring. The effects of cannabis on other physiological aspects of the developing fetus have received less attention. Importantly, our knowledge about cannabinoid signaling in the placenta is also limited. The endocannabinoid system (ECS) is present at early stages of development and represents a potential target for exogenous cannabinoids in utero. The ECS is expressed in a broad range of tissues and influences a spectrum of cellular functions. The aim of this review is to explore the current evidence surrounding the effects of prenatal exposure to cannabinoids and the role of the ECS in the placenta and the developing fetus.
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- 2021
12. Prenatal nicotine exposure leads to decreased histone H3 lysine 9 (H3K9) methylation and increased
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Sergio, Raez-Villanueva, Amrita, Debnath, Daniel B, Hardy, and Alison C, Holloway
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Histones ,Nicotine ,Src Homology 2 Domain-Containing, Transforming Protein 1 ,Pregnancy ,Lysine ,Animals ,Female ,Methylation ,Pancreas ,Rats - Abstract
Prenatal exposure to nicotine, tobacco's major addictive constituent, has been shown to reduce birth weight and increases apoptosis, oxidative stress, and mitochondrial dysfunction in the postnatal pancreas. Given that upregulated levels of the pro-oxidative adapter protein p66shc is observed in growth-restricted offspring and is linked to beta-cell apoptosis, the goal of this study was to investigate whether alterations in p66shc expression underlie the pancreatic deficits in nicotine-exposed offspring. Maternal administration of nicotine in rats increased p66shc expression in the neonatal pancreas. Similarly, nicotine treatment augmented p66shc expression in INS-1E pancreatic beta cells. Increased p66shc expression was also associated with decreased histone H3 lysine 9 methylation. Finally, nicotine increased the expression of Kdm4c, a key histone lysine demethylase, and decreased Suv39h1, a critical histone lysine methyltransferase. Collectively, these results suggest that upregulation of p66shc through posttranslational histone modifications may underlie the reported adverse outcomes of nicotine exposure on pancreatic function.
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- 2021
13. Low dose antibiotic ingestion potentiates systemic and microbiome changes induced by silver nanoparticles
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Azam F. Tayabali, Matthew J. Meier, Kathy C. Nguyen, Philip S. Shwed, Karen Leingartner, Michael G. Wade, M. Navarro, A. Wong, Alice Kawata, Marc Rigden, L.A. Beaudette, Jennifer Crosthwait, and Alison C. Holloway
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Silver ,medicine.drug_class ,Materials Science (miscellaneous) ,Antibiotics ,Metal Nanoparticles ,Biology ,Gut flora ,DNA, Ribosomal ,Microbiology ,Cecum ,Eating ,Mice ,Anti-Infective Agents ,Immunity ,medicine ,Ingestion ,Animals ,Microbiome ,Safety, Risk, Reliability and Quality ,Mammals ,Microbiota ,Public Health, Environmental and Occupational Health ,biology.organism_classification ,Antimicrobial ,Anti-Bacterial Agents ,medicine.anatomical_structure ,Safety Research ,Akkermansia muciniphila - Abstract
Changes in the mammalian gut microbiome are linked to the impairment of immunological function and numerous other pathologies. Antimicrobial silver nanoparticles (AgNPs) are incorporated into numerous consumer products (e.g., clothing, cosmetics, food packaging), which may directly impact the gut microbiome through ingestion. The human health impact of chronic AgNP ingestion is still uncertain, but evidence from exposure to other antimicrobials provides a strong rationale to assess AgNP effects on organ function, immunity, metabolism, and gut-associated microbiota. To investigate this, mice were gavaged daily for 5 weeks with saline, AgNPs, antibiotics (ciprofloxacin and metronidazole), or AgNPs combined with antibiotics. Animals were weighed daily, assessed for glucose tolerance, organ function, tissue and blood cytokine and leukocyte levels. At the end of the study, we used 16S rDNA amplicon and whole-metagenome shotgun sequencing to assess changes in the gut microbiome. In mice exposed to both AgNPs and antibiotics, silver was found in the stomach, and small and large intestines, but negligible amounts were present in other organs examined. Mice exposed to AgNPs alone showed minimal tissue silver levels. Antibiotics, but not AgNPs, altered glucose metabolism. Mice given AgNPs and antibiotics together demonstrated slower weight gain, reduced peripheral lymphocytes, and elevated splenic, but not circulatory markers of inflammation. 16S rDNA profiling of cecum and feces and metagenomic sequencing of fecal DNA demonstrated that combined AgNP-antibiotic treatment also significantly altered the structure and function of the gut microbiota, including depletion of the indicator species Akkermansia muciniphila. This study provides evidence for possible biological effects from repeated ingestion of AgNP-containing consumer products when antibiotics are also being used and raises concern that an impaired gut microbiome (e.g., through antibiotic use) can potentiate the harm from chemical exposures such as AgNPs.
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- 2021
14. The effects of oil sands process-affected water naphthenic acid fraction components on GDF15 secretion in extravillous trophoblast cells
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Laiba, Jamshed, Genevieve A, Perono, Lina R, Yacoub, Robert M, Gutgesell, Richard A, Frank, L Mark, Hewitt, Philippe J, Thomas, and Alison C, Holloway
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Inflammation ,Mammals ,Pharmacology ,Growth Differentiation Factor 15 ,Placenta ,Prostaglandins E ,Carboxylic Acids ,Water ,Toxicology ,Trophoblasts ,Cyclooxygenase 2 ,Pregnancy ,Prostaglandins ,Animals ,Humans ,Female ,Oil and Gas Fields ,Water Pollutants, Chemical ,Transcription Factors - Abstract
Exposure to compounds present in petroleum and wastewaters from oil and gas extraction sites in the Alberta Oil Sands Region can impair reproductive health. It has been established that acid extractable organics found in oil sands process-affected water (OSPW) such as naphthenic acids (NA-fraction components; NAFC) can adversely affect reproductive outcomes. We have shown that NAFC exposure results in a significant upregulation of GDF15 in placental trophoblasts, a cellular stress marker known to be involved in human embryonic development and necessary for the maintenance of pregnancy. However, little is known regarding the mechanism(s) underlying NAFC-induced increases in GDF15 production during early placentation. The goal of this study was to examine the effects of NAFC exposure on the regulation of critical transcription factors of GDF15 in extravillous trophoblast cells. Of these transcription factors, inflammatory mediators including prostaglandins have been reported to inhibit proliferation and migration of trophoblast cells in vitro. Hence, the secondary goal of this study was to determine whether inflammation mediated through prostaglandin production is critical to GDF15 secretion. HTR-8/SVneo cells were exposed to an NAFC for 6 and 24 h to assess the expression of key transcriptional regulators, GDF15 secretion, and prostaglandin (PGE
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- 2022
15. Gestational exposure to Δ
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Annia A, Martínez-Peña, Kendrick, Lee, James J, Petrik, Daniel B, Hardy, and Alison C, Holloway
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Disease Models, Animal ,Ovarian Follicle ,Maternal Exposure ,Pregnancy ,Prenatal Exposure Delayed Effects ,Animals ,Brain ,Angiogenesis Inducing Agents ,Female ,Dronabinol ,Rats, Wistar ,Rats - Abstract
With the legalization of marijuana (Cannabis sativa) and increasing use during pregnancy, it is important to understand its impact on exposed offspring. Specifically, the effects of Δ-9-tetrahydrocannabinol (Δ9-THC), the major psychoactive component of cannabis, on fetal ovarian development and long-term reproductive health are not fully understood. The aim of this study was to assess the effect of prenatal exposure to Δ9-THC on ovarian health in adult rat offspring. At 6 months of age, Δ9-THC-exposed offspring had accelerated folliculogenesis with apparent follicular development arrest, but no persistent effects on circulating steroid levels. Ovaries from Δ9-THC-exposed offspring had reduced blood vessel density in association with decreased expression of the pro-angiogenic factor VEGF and its receptor VEGFR-2, as well as an increase in the anti-angiogenic factor thrombospondin 1 (TSP-1). Collectively, these data suggest that exposure to Δ9-THC during pregnancy alters follicular dynamics during postnatal life, which may have long-lasting detrimental effects on female reproductive health.
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- 2021
16. Maternal exposure to Δ9-tetrahydrocannabinol impairs female offspring glucose homeostasis and endocrine pancreatic development in the rat
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Alison C. Holloway, Sebastian Vanin, Edith Arany, Kendrick Lee, Daniel B. Hardy, Ryan Gillies, and Steven R. Laviolette
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Male ,THC ,Offspring ,medicine.medical_treatment ,Medical Physiology ,Physiology ,010501 environmental sciences ,Toxicology ,01 natural sciences ,03 medical and health sciences ,Islets of Langerhans ,cannabinoids ,Pregnancy ,Medicine ,Endocrine system ,Glucose homeostasis ,Animals ,Homeostasis ,Insulin ,Dronabinol ,pancreas ,Rats, Wistar ,Maternal-Fetal Exchange ,030304 developmental biology ,0105 earth and related environmental sciences ,2. Zero hunger ,0303 health sciences ,Sex Characteristics ,business.industry ,beta cell mass ,DOHaD ,medicine.disease ,Pharmacy and Pharmaceutical Sciences ,3. Good health ,medicine.anatomical_structure ,Glucose ,fetal programming ,In utero ,Prenatal Exposure Delayed Effects ,Gestation ,Female ,Δ9-tetrahydrocannabinol ,pregnancy ,business ,Pancreas - Abstract
Recent reports indicate that 7% of pregnant mothers in North America use cannabis. This is concerning given that in utero exposure to Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive component in cannabis, causes fetal growth restriction and may alter replication and survival of pancreatic β-cells in the offspring. Accordingly, we hypothesized that maternal exposure to Δ9-THC during pregnancy will impair postnatal glucometabolic health of offspring. To test this hypothesis, pregnant Wistar rats were treated with daily intraperitoneal injections of either 3 mg/kg Δ9-THC or vehicle from gestational day 6 to birth. Offspring were subsequently challenged with glucose and insulin at 5 months of age to assess glucose tolerance and peripheral muscle insulin sensitivity. Female offspring exposed to Δ9-THC in utero were glucose intolerant, associated with blunted insulin response in muscle and increased serum insulin concentration 15 minutes after glucose challenge. Additionally, pancreata from male and female offspring were harvested at postnatal day 21 and 5 months of age for assessment of endocrine pancreas morphometry by immunostaining. This analysis revealed that gestational exposure to Δ9-THC reduced the density of islets in female, but not male, offspring at postnatal day 21 and 5 months, culminating in reduced β-cell mass at 5 months. These results demonstrate that fetal exposure to Δ9-THC causes female-specific impairments in glucose homeostasis, raising concern regarding the metabolic health of offspring, particularly females, exposed to cannabis in utero.
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- 2020
17. Maternal Nicotine Exposure Leads to Augmented Expression of the Antioxidant Adipose Tissue Triglyceride Lipase Long-Term in the White Adipose of Female Rat Offspring
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Daniel B. Hardy, Nicole G. Barra, Taylor A. Vanduzer, and Alison C. Holloway
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0301 basic medicine ,Nicotine ,medicine.medical_specialty ,Offspring ,Adipose Tissue, White ,Adipocytes, White ,Adipose tissue ,White adipose tissue ,Toxicology ,Antioxidants ,03 medical and health sciences ,chemistry.chemical_compound ,Pregnancy ,Adipocyte ,Internal medicine ,medicine ,Animals ,Lipolysis ,Rats, Wistar ,Nicotine replacement ,business.industry ,Escherichia coli Proteins ,Lipogenesis ,nutritional and metabolic diseases ,Lipase ,Maternal Nicotine Exposure and Adipose in Offspring ,3. Good health ,030104 developmental biology ,Endocrinology ,chemistry ,Maternal Exposure ,Prenatal Exposure Delayed Effects ,Adipose triglyceride lipase ,Female ,business ,medicine.drug - Abstract
Globally, approximately 10%–25% of women smoke during pregnancy. Since nicotine is highly addictive, women may use nicotine-containing products like nicotine replacement therapies for smoking cessation, but the long-term consequences of early life exposure to nicotine remain poorly defined. Our laboratory has previously demonstrated that maternal nicotine exposed (MNE) rat offspring exhibit hypertriglyceridemia due to increased hepatic de novo lipogenesis. Hypertriglyceridemia may also be attributed to impaired white adipose tissue (WAT) lipid storage; however, the effects of MNE on WAT are not completely understood. We hypothesize that nicotine-induced alterations in adipose function (eg, lipid storage) underlie dyslipidemia in MNE adults. Female 6-month-old rats exposed to nicotine during gestation and lactation exhibited significantly decreased visceral adipocyte cell area by 40%, attributed, in part, to a 3-fold increase in adipose triglyceride lipase (ATGL) protein expression compared with vehicle. Given ATGL has antioxidant properties and in utero nicotine exposure promotes oxidative stress in various tissues, we next investigated if there was evidence of increased oxidative stress in MNE WAT. At both 3 weeks and 6 months, MNE offspring expressed 37%–48% higher protein levels of superoxide dismutase-1 and -2 in WAT. Since oxidative stress can induce inflammation, we examined the inflammatory profile of WAT and found increased expression of cytokines (interleukin-1β, tumor necrosis factor α, and interleukin-6) by 44%–61% at 6 months. Collectively, this suggests that the expression of WAT ATGL may be induced to counter MNE-induced oxidative stress and inflammation. However, higher levels of ATGL would further promote lipolysis in WAT, culminating in impaired lipid storage and long-term dyslipidemia.
- Published
- 2018
18. Ozone modifies the metabolic and endocrine response to glucose: Reproduction of effects with the stress hormone corticosterone
- Author
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Josée Guénette, Alison C. Holloway, Andrew Williams, Errol M. Thomson, and Shinjini Pilon
- Subjects
Blood Glucose ,Male ,0301 basic medicine ,Hypothalamo-Hypophyseal System ,medicine.medical_specialty ,medicine.medical_treatment ,Pituitary-Adrenal System ,Toxicology ,Glucagon ,Impaired glucose tolerance ,03 medical and health sciences ,chemistry.chemical_compound ,Ozone ,Corticosterone ,Internal medicine ,medicine ,Animals ,Triglycerides ,Pharmacology ,Air Pollutants ,Glucose tolerance test ,medicine.diagnostic_test ,Chemistry ,Insulin ,Leptin ,medicine.disease ,Rats, Inbred F344 ,Rats ,Glucose ,030104 developmental biology ,Endocrinology ,Metabolic syndrome ,Glucocorticoid ,medicine.drug - Abstract
Air pollution is associated with increased incidence of metabolic disease (e.g. metabolic syndrome, obesity, diabetes); however, underlying mechanisms are poorly understood. Air pollutants increase the release of stress hormones (human cortisol, rodent corticosterone), which could contribute to metabolic dysregulation. We assessed acute effects of ozone, and stress axis involvement, on glucose tolerance and on the metabolic (triglyceride), endocrine/energy regulation (insulin, glucagon, GLP-1, leptin, ghrelin, corticosterone), and inflammatory/endothelial (TNF, IL-6, VEGF, PAI-1) response to exogenous glucose. Male Fischer-344 rats were exposed to clean air or 0.8 ppm ozone for 4 h in whole body chambers. Hypothalamic-pituitary-adrenal (HPA) axis involvement in ozone effects was tested through subcutaneous administration of the glucocorticoid synthesis inhibitor metyrapone (50 mg/kg body weight), corticosterone (10 mg/kg body weight), or vehicle (40% propylene glycol) prior to exposure. A glucose tolerance test (2 g/kg body weight glucose) was conducted immediately after exposure, with blood samples collected at 0, 30, 60, 90, and 120 min. Ozone exposure impaired glucose tolerance, an effect accompanied by increased plasma triglycerides but no impairment of insulin release. Ozone diminished glucagon, GLP-1, and ghrelin responses to glucose, but did not significantly impact inflammatory/endothelial analytes. Metyrapone reduced corticosterone but increased glucose and triglycerides, complicating evaluation of the impact of glucocorticoid inhibition. However, administration of corticosterone reproduced the profile of ozone effects, supporting a role for the HPA axis. The results show that ozone-dependent changes in glucose tolerance are accompanied by altered metabolic and endocrine responses to glucose challenge that are reproduced by exogenous stress hormone.
- Published
- 2018
19. Δ9-tetrahydrocannabinol exposure during rat pregnancy leads to symmetrical fetal growth restriction and labyrinth-specific vascular defects in the placenta
- Author
-
Steven R. Laviolette, Daniel B. Hardy, Bryony V. Natale, David R. C. Natale, Alison C. Holloway, Katarina Gustin, and Kendrick Lee
- Subjects
medicine.medical_treatment ,Placenta ,Medical Physiology ,lcsh:Medicine ,fetal growth restriction ,0302 clinical medicine ,Glucocorticoid receptor ,Pregnancy ,Dronabinol ,lcsh:Science ,reproductive and urinary physiology ,2. Zero hunger ,0303 health sciences ,Glucose Transporter Type 1 ,Multidisciplinary ,Fetal Growth Retardation ,biology ,Intrauterine growth ,Epithelial Cell Adhesion Molecule ,3. Good health ,Trophoblasts ,medicine.anatomical_structure ,Outcomes research ,embryonic structures ,Gestation ,Female ,placenta ,Intraperitoneal injection ,Article ,Andrology ,03 medical and health sciences ,Receptors, Glucocorticoid ,medicine ,Animals ,030304 developmental biology ,Fetus ,business.industry ,lcsh:R ,Trophoblast ,Pharmacy and Pharmaceutical Sciences ,medicine.disease ,Rats ,biology.protein ,Blood Vessels ,Glut-1 ,GLUT1 ,lcsh:Q ,Δ9-tetrahydrocannabinol ,business ,030217 neurology & neurosurgery - Abstract
1 in 5 women report cannabis use during pregnancy, with nausea cited as their primary motivation. Studies show that (-)-△9–tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient in cannabis, causes fetal growth restriction, though the mechanisms are not well understood. Given the critical role of the placenta to transfer oxygen and nutrients from mother, to the fetus, any compromise in the development of fetal-placental circulation significantly affects maternal-fetal exchange and thereby, fetal growth. The goal of this study was to examine, in rats, the impact of maternal Δ9-THC exposure on fetal development, neonatal outcomes, and placental development. Dams received a daily intraperitoneal injection (i.p.) of vehicle control or Δ9-THC (3 mg/kg) from embryonic (E)6.5 through 22. Dams were allowed to deliver normally to measure pregnancy and neonatal outcomes, with a subset sacrificed at E19.5 for placenta assessment via immunohistochemistry and qPCR. Gestational Δ9-THC exposure resulted in pups born with symmetrical fetal growth restriction, with catch up growth by post-natal day (PND)21. During pregnancy there were no changes to maternal food intake, maternal weight gain, litter size, or gestational length. E19.5 placentas from Δ9-THC-exposed pregnancies exhibited a phenotype characterized by increased labyrinth area, reduced Epcam expression (marker of labyrinth trophoblast progenitors), altered maternal blood space, decreased fetal capillary area and an increased recruitment of pericytes with greater collagen deposition, when compared to vehicle controls. Further, at E19.5 labyrinth trophoblast had reduced glucose transporter 1 (GLUT1) and glucocorticoid receptor (GR) expression in response to Δ9-THC exposure. In conclusion, maternal exposure to Δ9-THC effectively compromised fetal growth, which may be a result of the adversely affected labyrinth zone development. These findings implicate GLUT1 as a Δ9-THC target and provide a potential mechanism for the fetal growth restriction observed in women who use cannabis during pregnancy.
- Published
- 2019
20. Quantifying cellular protrusion in alginate capsules with covalently crosslinked shells
- Author
-
Harald D. H. Stöver, Nicholas A. D. Burke, Ahmed Ayyash, Shanna Shi, Mitchell Johnson, Rachelle M. Kleinberger, Alison C. Holloway, Nicole Latchminarine, and Ali Abu Helal
- Subjects
Alginates ,Cell Survival ,Confocal ,Cell ,Pharmaceutical Science ,Bioengineering ,Capsules ,02 engineering and technology ,engineering.material ,030226 pharmacology & pharmacy ,Cell Line ,Micrometre ,03 medical and health sciences ,0302 clinical medicine ,Colloid and Surface Chemistry ,Coating ,Insulin-Secreting Cells ,medicine ,Animals ,Polylysine ,Physical and Theoretical Chemistry ,Cell encapsulation ,Maleic Anhydrides ,Chemistry ,Organic Chemistry ,Colocalization ,Capsule ,Cells, Immobilized ,021001 nanoscience & nanotechnology ,Rats ,medicine.anatomical_structure ,Cross-Linking Reagents ,Covalent bond ,engineering ,Biophysics ,Cell Surface Extensions ,0210 nano-technology ,Gels - Abstract
This work describes viability and distribution of INS-1E beta cells in shell-crosslinked alginate capsules, focussing on cells located near the capsule surface. Capsules were formed by air-shearing alginate suspensions of INS-1E cells into a gelling bath, and coating with poly-l-lysine (PLL) and 50% hydrolysed poly(methylvinylether-alt-maleic anhydride) to form crosslinked networks reinforcing the capsule surfaces. The percentage of cells at the capsule surface were determined using 2D and 3D confocal colocalization mapping. Encapsulated INS-1E cells showed high cell viability and progressive cell clustering out to six weeks. About 30% of cells were initially colocated with the 20 micrometer thick alginate-PLL-PMM50 shell, with 7% of cells protruded at the capsule surfaces, both reflecting random cell distributions. Protruding cells may cause cell-based immune responses, weaken capsules, and potentially result in cell escape from the capsules. The data shown indicate that reinforcing capsules with crosslinked shells may assist in preventing cell exposure and escape.
- Published
- 2019
21. Toxicity of Flame Retardant Isopropylated Triphenyl Phosphate: Liver, Adrenal, and Metabolic Effects
- Author
-
Don Caldwell, Alice Kawata, Alison C. Holloway, Michael G. Wade, and Marc Rigden
- Subjects
Male ,medicine.medical_specialty ,medicine.medical_treatment ,010501 environmental sciences ,Toxicology ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Corticosterone ,Internal medicine ,medicine ,Cytochrome P-450 CYP1A1 ,Endocrine system ,Animals ,Rats, Wistar ,030304 developmental biology ,0105 earth and related environmental sciences ,Flame Retardants ,0303 health sciences ,Adrenal gland ,Adrenal cortex ,Cholesterol ,Insulin ,Organophosphate ,Lipid Metabolism ,Organophosphates ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Liver ,Toxicity ,Cytochrome P-450 CYP2B1 ,Adrenal Cortex ,Female - Abstract
The use of organophosphates phosphate flame retardants, particularly isopropylated triphenyl phosphate (IPTPP), has increased in recent years as replacements for polybrominated diphenyl ethers. This is despite limited understanding of the hazards of IPTPP. To examine the general and endocrine toxicity of IPTPP, adult Wistar rats were fed for 90 days on diets containing IPTPP estimated to deliver daily doses of 5 to 140 mg/kg/d. Exposure to IPTPP caused a dose-related increase in liver and adrenal gland weight in both sexes. Cells in the zona fasciculate (ZF) of the adrenal cortex were observed to be filled with droplets that stained with Nile red, suggesting they contained neutral lipid. Despite marked structural changes, there was no change in basal or stress-induced serum levels of their major secreted ZF product corticosterone (B), suggesting cell function was not altered. There were no effects on responses to glucose or insulin challenge, but serum levels of fructosamine were elevated by IPTPP exposure, suggesting a slight tendency of exposed animals to be hyperglycemic. Serum levels of total cholesterol and high-density lipoprotein cholesterol were significantly elevated in both sexes at the 2 highest doses. This study demonstrates that IPTPP exposure causes hypertrophy and neutral lipid accumulation in adrenal cortex ZF cells but does not result in impaired B production.
- Published
- 2019
22. The role of the endocannabinoid system in female reproductive tissues
- Author
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Alison C. Holloway, O’Llenecia S. Walker, and Sandeep Raha
- Subjects
0301 basic medicine ,Hypothalamo-Hypophyseal System ,Cannabinoid receptor ,Endocannabinoid system ,medicine.medical_treatment ,Review ,Biology ,lcsh:Gynecology and obstetrics ,03 medical and health sciences ,0302 clinical medicine ,Ovarian cancer ,Female reproduction ,medicine ,PCOS ,Animals ,Humans ,Ovarian Diseases ,Receptor ,lcsh:RG1-991 ,Cannabis ,Reproduction ,Ovary ,Obstetrics and Gynecology ,Placentation ,Decidualization ,3. Good health ,Cell biology ,Crosstalk (biology) ,Steroid hormone ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,lipids (amino acids, peptides, and proteins) ,Female ,Cannabinoid ,Endocannabinoids - Abstract
There has been increasing interest in the role of endocannabinoids as critical modulators of the female reproductive processes. Endocannabinoids are natural ligands of cannabinoid, vanilloid, and peroxisome proliferator-activated receptors. Together with their receptors, enzymes and downstream signaling targets, they form the endocannabinoid system (ECS). While the ECS is known to modulate pain and neurodevelopment, it is also known to impact the female reproductive system where it affects folliculogenesis, oocyte maturation, and ovarian endocrine secretion. In addition, the ECS affects oviductal embryo transport, implantation, uterine decidualization and placentation. There is a complex interplay between the ECS and the hypothalamic-pituitary-ovarian axis, and an intricate crosstalk between the ECS and steroid hormone production and secretion. Exogenous cannabinoids, derived from plants such as Cannabis sativa, are also ligands for cannabinoid receptors. These have been shown to have clinical outcomes related to ECS dysregulation, including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis, along with adverse effects on female reproduction. The aim of this review is to describe and discuss data from human, animal, and in vitro studies that support the important role of the endocannabinoid system in female reproductive tissues and processes. In particular, we will discuss some of the mechanisms by which endocannabinoid signaling can affect ovarian function in both physiological and pathophysiological states.
- Published
- 2019
23. Co-exposures to trace elements and polycyclic aromatic compounds (PACs) impacts North American river otter (Lontra canadensis) baculum
- Author
-
Zhe Xia, Kristin M. Eccles, Elizabeth A. Hassan, Alison C. Holloway, Emily E. Newell, Ifeoluwa Idowu, Philippe J. Thomas, Gregg T. Tomy, and Cheryl E. Quenneville
- Subjects
Male ,Environmental Engineering ,Health, Toxicology and Mutagenesis ,Sentinel species ,0208 environmental biotechnology ,Zoology ,02 engineering and technology ,010501 environmental sciences ,01 natural sciences ,North American river otter ,Alberta ,Biomonitoring ,Lontra ,Animals ,Environmental Chemistry ,Oil and Gas Fields ,Polycyclic Compounds ,14. Life underwater ,Ecosystem ,0105 earth and related environmental sciences ,River otter ,geography.river ,geography ,Reproductive success ,biology ,Public Health, Environmental and Occupational Health ,General Medicine ,General Chemistry ,biology.organism_classification ,Pollution ,Trace Elements ,020801 environmental engineering ,13. Climate action ,Baculum ,Reproductive toxicity ,Environmental Monitoring ,Otters - Abstract
Environmental loadings of polycyclic aromatic compounds (PACs) and trace elements are increasing in areas with marked oil and gas extraction, such as in the Athabasca oil sands region, Alberta, Canada. Some of these chemicals are recognized as potent endocrine disrupting compounds (EDCs). The impacts of co-exposure to PACs and metals on free-ranging wildlife is of considerable concern. River otters (Lontra canadensis) are sentinel species of aquatic ecosystem health. The baculum (penile bone) is an important part of the reproductive system in otters that ensures successful copulation. Although baculum health is critical to male reproductive success and is sensitive to exposure to EDCs, there is no information available regarding the impact of PAC and metal exposures on measures of baculum health. River otter baculum and livers were dissected from carcasses obtained from the fur trade. Trace element and PAC analyses were carried out in liver with matching baculums subjected to dimensional analysis, bone mineral density (BMD) and mechanical loading testing. Trace elements and select PACs exhibited both protective and deleterious effects on baculum bone health metrics. Alkylated four ring PACs were negatively associated with baculum bone material properties (ex: C4-Chrysene and C4-pyrene). The same compounds have been shown to exhibit strong anti-androgenic activities. Few comparable studies exist related to contamination and adverse effects of PACs in wild terrestrial mammals. Baculum health metrics may be an important tool to include in biomonitoring studies as to date, there are limited means to assess male reproductive performance in wildlife biomonitoring programs.
- Published
- 2021
24. Vape flavourants dull sensory perception and cause hyperactivity in developing zebrafish embryos
- Author
-
Alison C. Holloway, Patrick T. Gauthier, and Mathilakath M. Vijayan
- Subjects
Nicotine ,media_common.quotation_subject ,Electronic Nicotine Delivery Systems ,010501 environmental sciences ,Pharmacology ,01 natural sciences ,03 medical and health sciences ,Perception ,medicine ,Animals ,Prenatal exposure ,Zebrafish ,Brain function ,030304 developmental biology ,0105 earth and related environmental sciences ,media_common ,0303 health sciences ,biology ,Vaping ,Neurotoxicity ,biology.organism_classification ,medicine.disease ,Agricultural and Biological Sciences (miscellaneous) ,Chemical constituents ,Zebrafish embryo ,Animal Behaviour ,General Agricultural and Biological Sciences ,medicine.drug - Abstract
E-cigarette use (vaping) during pregnancy has been increasing, and the potential exists for the developing brainin uteroto be exposed to chemical constituents in the vape. Vapes come in over 7000 unique flavours with and without nicotine, and while nicotine is a known neurotoxicant, the effects of vape flavouring alone, in the absence of nicotine, on brain function are not well understood. Here, we performed a screen of vape aerosol extracts (VAEs) to determine the potential for prenatal neurotoxicity using the zebrafish embryo photomotor response (PMR)—a translational biosensor of neurobehavioural effects. We screened three commonly used aerosolized vape liquids (flavoured and flavourless) either with or without nicotine. No neurobehavioural effects were detected in flavourless, nicotine-free VAEs, while the addition of nicotine to this VAE dulled sensory perception. Flavoured nicotine-free VAEs also dulled sensory perception and caused hyperactivity in zebrafish embryos. The combination of flavour and nicotine produced largely additive effects. Flavoured VAEs without nicotine had similar neuroactive potency to nicotine. Together, using zebrafish PMR as a high throughput translational behavioural model for prenatal exposure, our results demonstrate that e-cigarette flavourants that we screened elicit neurobehavioural effects worthy of further investigation for long-term neurotoxic potential and also have the potential to modulate nicotine impact on the developing brain.
- Published
- 2020
25. Antenatal exposure to the selective serotonin reuptake inhibitor fluoxetine leads to postnatal metabolic and endocrine changes associated with type 2 diabetes in Wistar rats
- Author
-
Christopher J. Pinelli, Nicole E. De Long, Alison C. Holloway, Valerie H. Taylor, Eric J. Barry, Daniel B. Hardy, Katherine M. Morrison, Hertzel C. Gerstein, and Geoffrey A. Wood
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,Time Factors ,Offspring ,Serotonin reuptake inhibitor ,Biology ,Weight Gain ,Toxicology ,Risk Assessment ,Fluoxetine Hydrochloride ,Sex Factors ,Non-alcoholic Fatty Liver Disease ,Pregnancy ,Fluoxetine ,Internal medicine ,medicine ,Animals ,Glucose homeostasis ,Rats, Wistar ,Chemokine CCL2 ,Adiposity ,Dyslipidemias ,Metabolic Syndrome ,Pharmacology ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Fatty liver ,medicine.disease ,Endocrinology ,Diabetes Mellitus, Type 2 ,Liver ,Maternal Exposure ,Prenatal Exposure Delayed Effects ,Antidepressant ,Female ,Chemical and Drug Induced Liver Injury ,Selective Serotonin Reuptake Inhibitors ,medicine.drug - Abstract
Hypothesis 10–15% of women take antidepressant medications during pregnancy. A recent clinical study reported that the use of selective serotonin reuptake inhibitor antidepressants during pregnancy is linked with an increased risk of postnatal obesity. While obesity is often associated with fatty liver, dyslipidemia and inflammation, to date, the effects of perinatal exposure to SSRIs on these outcomes are unknown. Methods Female nulliparous Wistar rats were given vehicle (N = 15) or fluoxetine hydrochloride (FLX 10 mg/kg/d; N = 15) orally for 2 weeks prior to mating until weaning. We assessed glucometabolic changes and hepatic pathophysiology in the offspring. Results Fluoxetine exposed offspring demonstrated altered glucose homeostasis without any alterations to beta cell mass. FLX-exposed offspring had a significant increase in the number of offspring with mild to moderate NASH and dyslipidemia. There was also increased inflammation of the liver in FLX-exposed offspring; males had significant elevations in TNFα, IL6 and monocyte chemoattractant protein 1 (MCP1), while female offspring had higher expression of TNFα, and increased macrophage infiltration (MCP1). Limitations This is an animal study. Further research examining the metabolic outcomes of children exposed to antidepressants in utero are required, given the increase in childhood obesity and psychiatric medication use during pregnancy. Conclusion These data demonstrate that fetal and neonatal exposure to FLX results in evidence of increased adiposity, fatty liver and abnormal glycemic control. Since these are all hallmarks of the metabolic syndrome, this raises concerns regarding the long term metabolic sequelae of fetal exposure to SSRIs in human populations.
- Published
- 2015
26. Major Depressive Disorder and Diabetes: Does Serotonin Bridge the Gap?
- Author
-
Rebecca A. Stepita, Nicole E. De Long, Alison C. Holloway, and Valerie H. Taylor
- Subjects
Serotonin ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Type 2 diabetes ,Weight Gain ,Bioinformatics ,Serotonergic ,Endocrinology ,Risk Factors ,Insulin-Secreting Cells ,Diabetes mellitus ,Internal medicine ,medicine ,Animals ,Humans ,Glucose homeostasis ,Depressive Disorder, Major ,business.industry ,medicine.disease ,Antidepressive Agents ,Diabetes Mellitus, Type 2 ,Major depressive disorder ,Antidepressant ,Serotonin Antagonists ,Insulin Resistance ,Reuptake inhibitor ,business ,Selective Serotonin Reuptake Inhibitors - Abstract
Major depressive disorder (MDD) is one of the most common psychiatric illnesses worldwide, with reported prevalence rates ranging between 10% and 19%. Pharmacotherapy is a first-line option for the management of MDD and, as a result, the use of antidepressants has increased 4 fold in the last 20 years. Serotonin is the most commonly dysregulated neurotransmitter in the etiology of MDD and this system is the primary focus of most medications used in the treatment of illness. Although antidepressant use in adults increases the risk of developing new onset type 2 diabetes, the mechanisms underlying this association are poorly defined. This review will focus on 1) the evidence from human and animal studies suggesting a link between the use of antidepressants that target serotonin signaling (i.e., SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin antagonist and reuptake inhibitors (SARIs), and noradrenergic and specific serotonergic antidepressants (NaSSAs)) and increased risk of diabetes, and 2) the mechanisms by which alterations in serotonin signalling by antidepressants can affect glucose homeostasis.
- Published
- 2015
27. Is it safe to use smoking cessation therapeutics during pregnancy?
- Author
-
Nicole G. Barra, Alison C. Holloway, Nicole E. De Long, and Daniel B. Hardy
- Subjects
medicine.medical_specialty ,medicine.medical_treatment ,media_common.quotation_subject ,Nicotine ,chemistry.chemical_compound ,Pregnancy ,Quinoxalines ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Varenicline ,Psychiatry ,Intensive care medicine ,Bupropion ,media_common ,business.industry ,Addiction ,Smoking ,General Medicine ,Benzazepines ,medicine.disease ,Nicotine replacement therapy ,chemistry ,Smoking cessation ,Female ,Smoking Cessation ,business ,Drugs in pregnancy ,medicine.drug - Abstract
Introduction: Worldwide, 10 to 35% of pregnant women smoke. It is clear that smoking cessation has positive impacts for both the mother and child, yet many women are still unable to quit due to the addictive properties of nicotine. There are limited data surrounding their safety and efficacy in pregnancy.Areas covered: This review highlights evidence from clinical studies and animal experiments regarding the effects of smoking cessation therapeutics on pregnancy, neonatal and long-term postnatal outcomes.Expert opinion: There are insufficient data at this time to recommend the use of varenicline and/or bupropion for smoking cessation during pregnancy. In addition, the efficacy and safety of nicotine replacement therapy use for smoking cessation in pregnant women has not been clearly demonstrated. Until further studies are completed, there will continue to be considerable uncertainty regarding the use of these drugs in pregnancy despite the well-documented benefits of smoking cessation.
- Published
- 2014
28. Maternal nicotine exposure leads to decreased cardiac protein disulfide isomerase and impaired mitochondrial function in male rat offspring
- Author
-
Maria Lisyansky, Taylor A. Vanduzer, Alison C. Holloway, Sandeep Raha, Nicole G. Barra, and Daniel B. Hardy
- Subjects
0301 basic medicine ,Cardiac function curve ,Nicotine ,medicine.medical_specialty ,Offspring ,Medical Physiology ,Protein Disulfide-Isomerases ,PDI ,heart ,Biology ,Mitochondrion ,Toxicology ,Mitochondria, Heart ,Mitochondrial Proteins ,Superoxide dismutase ,reproduction ,03 medical and health sciences ,Pregnancy ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Protein disulfide-isomerase ,Nicotine replacement ,Myocardium ,Endoplasmic reticulum ,Pharmacy and Pharmaceutical Sciences ,3. Good health ,mitochondria ,Reproductive and Urinary Physiology ,030104 developmental biology ,Endocrinology ,Animals, Newborn ,Maternal Exposure ,Prenatal Exposure Delayed Effects ,biology.protein ,Female ,medicine.drug ,nicotine - Abstract
Smoking throughout pregnancy can lead to complications during gestation, parturition and neonatal development. Thus, nicotine replacement therapies are a popular alternative thought to be safer than cigarettes. However, recent studies in rodents suggest that fetal and neonatal nicotine exposure alone results in cardiac dysfunction and high blood pressure. While it is well known that perinatal nicotine exposure causes increased congenital abnormalities, the mechanisms underlying longer-term deficits in cardiac function are not completely understood. Recently, our laboratory demonstrated that nicotine impairs placental protein disulfide isomerase (PDI) triggering an increase in endoplasmic reticulum stress, leading us to hypothesize that this may also occur in the heart. At 3 months of age, nicotine-exposed offspring had 45% decreased PDI levels in the absence of endoplasmic reticulum stress. Given the association of PDI and superoxide dismutase enzymes, we further observed that antioxidant superoxide dismutase-2 levels were reduced by 32% in these offspring concomitant with a 26-49% decrease in mitochondrial complex proteins (I, II, IV and V) and tissue inhibitor of metalloproteinase-4, a critical matrix metalloprotease for cardiac contractility and health. Collectively, this study suggests that perinatal nicotine exposure decreases PDI, which can promote oxidative damage and mitochondrial damage, associated with a premature decline in cardiac function.
- Published
- 2017
29. Increased incidence of non-alcoholic fatty liver disease in male rat offspring exposed to fluoxetine during fetal and neonatal life involves the NLRP3 inflammasome and augmented de novo hepatic lipogenesis
- Author
-
Nicole E. De Long, Noelle Ma, Daniel B. Hardy, and Alison C. Holloway
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Transcription, Genetic ,Inflammasomes ,Offspring ,Medical Physiology ,Biology ,Toxicology ,behavioral disciplines and activities ,Epigenesis, Genetic ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Pregnancy ,inflammasome ,Fluoxetine ,Internal medicine ,NLR Family, Pyrin Domain-Containing 3 Protein ,mental disorders ,medicine ,Animals ,SSRI ,Rats, Wistar ,Fetus ,Triglyceride ,epigenetics ,Incidence ,Lipogenesis ,Fatty liver ,digestive, oral, and skin physiology ,dyslipidemia ,Inflammasome ,medicine.disease ,Pharmacy and Pharmaceutical Sciences ,Reproductive and Urinary Physiology ,030104 developmental biology ,Endocrinology ,Animals, Newborn ,chemistry ,Prenatal Exposure Delayed Effects ,Female ,Metabolic syndrome ,Selective Serotonin Reuptake Inhibitors ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Up to 10% of women take selective serotonin reuptake inhibitors (SSRI) during pregnancy. Children exposed to SSRIs in utero have an increased risk of being overweight suggesting that fetal exposure to SSRIs can cause permanent metabolic changes. We have previously shown in rats that fetal and neonatal exposure to the SSRI antidepressant fluoxetine results in metabolic perturbations including increased hepatic triglyceride content; a hallmark of non-alcoholic fatty liver disease (NAFLD). Therefore, the aim of this study was to identify the mechanism(s) underlying the fluoxetine-induced increase in intrahepatic triglyceride content. Female nulliparous Wistar rats were given vehicle or fluoxetine (10 mg/kg/day) orally for 2 weeks prior to mating until weaning. At 6 months of age, we assessed whether SSRI exposure altered components of the hepatic triglyceride biosynthesis pathway in the offspring and examined the molecular mechanisms underlying these changes. Male SSRI-exposed offspring had a significant increase in the steady-state mRNA levels of Elovl6 and Dgat1 and core components of the NLRP3 inflammasome (apoptosis-associated speck-like protein containing a caspase activation recruitment domain [ASC] and caspase-1). Augmented expression of Asc in the SSRI-exposed offspring coincided with increased histone acetylation in the proximal promoter region. Given that we have previously demonstrated that antenatal exposure to SSRIs can lead to fatty liver in the offspring, this raises concerns regarding the long-term metabolic sequelae of fetal SSRI exposure. Moreover, this study suggests that elevated hepatic triglyceride levels observed in the SSRI-exposed offspring may be due, in part, to activation of the NLRP3 inflammasome and augmentation of de novo lipogenesis.
- Published
- 2017
30. Fetal and neonatal exposure to nicotine leads to augmented hepatic and circulating triglycerides in adult male offspring due to increased expression of fatty acid synthase
- Author
-
Daniel B. Hardy, Noelle Ma, Alison C. Holloway, Michael K. Wong, and Catherine J. Nicholson
- Subjects
Male ,Nicotine ,medicine.medical_specialty ,Offspring ,Biology ,Response Elements ,Toxicology ,Histones ,Random Allocation ,Pregnancy ,Internal medicine ,Lactation ,medicine ,Animals ,Nicotinic Agonists ,Rats, Wistar ,Promoter Regions, Genetic ,Liver X receptor ,Liver X Receptors ,Hypertriglyceridemia ,Pharmacology ,Fetus ,Lipogenesis ,Acetylation ,Orphan Nuclear Receptors ,Nicotine replacement therapy ,medicine.disease ,Rats ,Up-Regulation ,Fatty acid synthase ,medicine.anatomical_structure ,Endocrinology ,Animals, Newborn ,Liver ,Prenatal Exposure Delayed Effects ,biology.protein ,Female ,Fatty Acid Synthases ,Protein Processing, Post-Translational ,medicine.drug - Abstract
While nicotine replacement therapy is assumed to be a safer alternative to smoking during pregnancy, the long-term consequences for the offspring remain elusive. Animal studies now suggest that maternal nicotine exposure during perinatal life leads to a wide range of adverse outcomes for the offspring including increased adiposity. The focus of this study was to investigate if nicotine exposure during pregnancy and lactation leads to alterations in hepatic triglyceride synthesis. Female Wistar rats were randomly assigned to receive daily subcutaneous injections of saline (vehicle) or nicotine bitartrate (1 mg/kg/day) for two weeks prior to mating until weaning. At postnatal day 180 (PND 180), nicotine exposed offspring exhibited significantly elevated levels of circulating and hepatic triglycerides in the male offspring. This was concomitant with increased expression of fatty acid synthase (FAS), the critical hepatic enzyme in de novo triglyceride synthesis. Given that FAS is regulated by the nuclear receptor Liver X receptor (LXRα), we measured LXRα expression in both control and nicotine-exposed offspring. Nicotine exposure during pregnancy and lactation led to an increase in hepatic LXRα protein expression and enriched binding to the putative LXRE element on the FAS promoter in PND 180 male offspring. This was also associated with significantly enhanced acetylation of histone H3 [K9,14] surrounding the FAS promoter, a hallmark of chromatin activation. Collectively, these findings suggest that nicotine exposure during pregnancy and lactation leads to an increase in circulating and hepatic triglycerides long-term via changes in the transcriptional and epigenetic regulation of the hepatic lipogenic pathway.
- Published
- 2014
31. Gestational and Lactational Exposure to an Environmentally-Relevant Mixture of Brominated Flame Retardants: Effects on Neurodevelopment and Metabolism
- Author
-
Emily W Y, Tung, Alice, Kawata, Marc, Rigden, Wayne J, Bowers, Don, Caldwell, Alison C, Holloway, Bernard, Robaire, Barbara F, Hales, and Michael G, Wade
- Subjects
Male ,polybrominated diphenyl ethers ,Halogenation ,neurodevelopment ,glucose tolerance ,Reproduction ,Environment ,Lipid Metabolism ,brominated flame retardants ,Hydrocarbons, Brominated ,Rats ,Rats, Sprague-Dawley ,Maternal Exposure ,Neurodevelopmental Disorders ,Pregnancy ,Prenatal Exposure Delayed Effects ,Halogenated Diphenyl Ethers ,hexabromocyclododecane ,Animals ,Lactation ,Female ,Research Articles ,Flame Retardants ,Research Article - Abstract
Background Developmental exposure to brominated flame retardants (BFRs), including polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCDD), has been associated with impaired neurodevelopment and some symptoms of metabolic syndrome. However, there are inconsistencies in studies reporting neurodevelopmental effects with studies of pure substances more likely to report effects than studies of technical products. In addition, the influence of early BFR exposures on later development of metabolic disease‐like symptoms has not been investigated. This study examined the effects of perinatal exposure to an environmentally relevant mixture of BFRs based on relative levels observed in house dust, on several markers of neurodevelopment and metabolism in offspring. Methods Sprague–Dawley female rats were fed a diet estimated to deliver daily doses of 0, 0.06, 20, or 60 mg/kg of a mixture of PBDEs and HBCDD from before mating to weaning. Offspring were weaned to control diet and subjected to neurobehavioral and metabolic assessments. Results Exposure to BFRs decreased vertical movement in at postnatal day (PND) 32 and increased time to emerge to a lighted area on PND 105 in offspring of both sexes. Although early life exposure to the BFR mixture did not impact measures of glucose or insulin action, male offspring had significantly decreased fat pad weights at PND 46. Total cholesterol was increased in male and female offspring exposed to the highest dose at PND 21. Conclusions These results suggest that gestational and lactational exposure to an environmentally relevant BFR mixture may induce changes in neurodevelopment and lipid metabolism in offspring. Birth Defects Research 109:497–512, 2017.© 2017 The Authors Birth Defects Research Published by Wiley Periodicals, Inc.
- Published
- 2016
32. Ozone Inhalation Provokes Glucocorticoid-Dependent and -Independent Effects on Inflammatory and Metabolic Pathways
- Author
-
Josée Guénette, Michael G. Wade, Shinjini Pal, Andrew Williams, Errol M. Thomson, Ella Atlas, Renaud Vincent, and Alison C. Holloway
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Pyridines ,Inflammation ,010501 environmental sciences ,Toxicology ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Ozone ,Corticosterone ,Internal medicine ,Adrenal Glands ,medicine ,Animals ,Cognitive decline ,Steroid 11-beta-hydroxylase ,Enzyme Inhibitors ,0105 earth and related environmental sciences ,Inhalation exposure ,Air Pollutants ,Inhalation Exposure ,Inhalation ,Metyrapone ,business.industry ,Pneumonia ,Rats, Inbred F344 ,Up-Regulation ,030104 developmental biology ,Endocrinology ,chemistry ,Cytokines ,Steroid 11-beta-Hydroxylase ,medicine.symptom ,Inflammation Mediators ,business ,Energy Metabolism ,Glucocorticoid ,Biomarkers ,medicine.drug - Abstract
Growing evidence implicates air pollutants in adverse health effects beyond respiratory and cardiovascular disease, including metabolic impacts (diabetes, metabolic syndrome, obesity) and neurological/neurobehavioral outcomes (neurodegenerative disease, cognitive decline, perceived stress, depression, suicide). We have shown that inhalation of particulate matter or ozone activates the hypothalamic-pituitary-adrenal axis in rats and increases plasma levels of the glucocorticoid corticosterone. To investigate the role of corticosterone in mediating inflammatory and metabolic effects of pollutant exposure, in this study male Fischer-344 rats were administered the 11β-hydroxylase inhibitor metyrapone (0, 50, 150 mg/kg body weight) and exposed by nose-only inhalation for 4 h to air or 0.8 ppm ozone. Ozone inhalation provoked a 2-fold increase in plasma corticosterone, an effect blocked by metyrapone, but did not alter epinephrine levels. Inhibition of corticosterone production was associated with increased inflammatory signaling in the lungs and plasma in response to ozone, consistent with a role for glucocorticoids in limiting local and systemic inflammatory responses. Effects of ozone on insulin and glucagon, but not ghrelin or plasminogen activator inhibitor-1, were modified by metyrapone, revealing glucocorticoid-dependent and -independent effects on circulating metabolic and hemostatic factors. Several immunosuppressive and metabolic impacts of ozone in the lungs, heart, liver, kidney, and spleen were blocked by metyrapone and reproduced through exogenous administration of corticosterone (10 mg/kg body weight), demonstrating glucocorticoid-dependent effects in target tissues. Our results support involvement of endogenous glucocorticoids in ozone-induced inflammatory and metabolic effects, providing insight into potential biological mechanisms underlying health impacts and susceptibility.
- Published
- 2016
33. Adverse effects of perinatal nicotine exposure on reproductive outcomes
- Author
-
Nicole G. Barra, Daniel B. Hardy, Michael K. Wong, Nadia Alfaidy, Alison C. Holloway, Invasion mechanisms in angiogenesis and cancer (IMAC), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
- Subjects
Embryology ,medicine.medical_specialty ,Nicotine ,Smoking Prevention ,Electronic Nicotine Delivery Systems ,Bioinformatics ,Risk Assessment ,Toxicology ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Fetus ,Pregnancy ,Risk Factors ,medicine ,Animals ,Humans ,Nicotinic Agonists ,Adverse effect ,Maternal Behavior ,030304 developmental biology ,Reproductive health ,Nicotine replacement ,0303 health sciences ,030219 obstetrics & reproductive medicine ,business.industry ,Public health ,Smoking ,Obstetrics and Gynecology ,[SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology ,Cell Biology ,medicine.disease ,Endoplasmic Reticulum Stress ,Tobacco Use Cessation Devices ,3. Good health ,Pregnancy Complications ,Oxidative Stress ,Reproductive Medicine ,Prenatal Exposure Delayed Effects ,Unfolded Protein Response ,Female ,Animal studies ,Inflammation Mediators ,business ,medicine.drug - Abstract
Nicotine exposure during pregnancy through cigarette smoking, nicotine replacement therapies or e-cigarette use continues to be a widespread public health problem, impacting both fetal and postnatal health. Yet, at this time, there remains limited data regarding the safety and efficacy in using these nicotine products during pregnancy. Notably, reports assessing the effect of nicotine exposure on postnatal health outcomes in humans, including reproductive health, are severely lacking. Our current understanding regarding the consequences of nicotine exposure during pregnancy is limited to a few animal studies, which do not comprehensively address the underlying cellular mechanisms involved. This paper aims to critically review the current knowledge from human and animal studies regarding the direct and indirect effects (e.g. obesity) of maternal nicotine exposure, regardless of its source, on reproductive outcomes in pregnancy and postnatal life. Furthermore, this review highlights several key cellular mechanisms involved in these adverse reproductive deficits including oxidative stress, inflammation, and endoplasmic reticulum (ER) stress. By understanding the interplay of the cellular mechanisms involved, further strategies could be developed to prevent the reproductive abnormalities resulting from exposure to nicotinein uteroand influence informed clinical guidelines for pregnant women.
- Published
- 2015
34. Adverse metabolic effects of a hypercaloric, high-fat diet in rodents precede observable changes in body weight
- Author
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Andrew C. Don-Wauchope, Hala El Zimaity, Eric Pesarchuk, Sarah D. McDonald, and Alison C. Holloway
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Intra-Abdominal Fat ,Biology ,Diet, High-Fat ,Impaired glucose tolerance ,chemistry.chemical_compound ,Endocrinology ,High-density lipoprotein ,Glucagon-Like Peptide 1 ,Non-alcoholic Fatty Liver Disease ,Hyperinsulinism ,Internal medicine ,Nonalcoholic fatty liver disease ,Hyperinsulinemia ,medicine ,Animals ,Insulin ,Weaning ,Obesity ,Rats, Wistar ,Triglycerides ,Adiposity ,Glucose tolerance test ,Nutrition and Dietetics ,medicine.diagnostic_test ,Body Weight ,nutritional and metabolic diseases ,Glucose Tolerance Test ,medicine.disease ,Dietary Fats ,Rats ,Fatty Liver ,Disease Models, Animal ,Glycemic index ,chemistry ,Glycemic Index ,Hyperglycemia ,hormones, hormone substitutes, and hormone antagonists - Abstract
Although a high-fat diet (HFD) is recognized as an important contributor to obesity, human research is limited by confounders such as income, whereas animal research has typically examined diet during specific developmental periods rather than throughout the lifespan. We hypothesized that the use of an HFD in short-term studies as has been commonly done in animals does not adequately reflect the lifelong dietary patterns seen frequently in humans with consequent metabolic disturbances. We examined the impact of HFD from weaning until 39 weeks (middle age) on the metabolism of male rats. At 7, 26, and 39 weeks, glucose tolerance tests were performed, a subset of animals was euthanized, and serum and tissues were collected. After 4 weeks, preceding increased body weight, HFD animals had increased intra-abdominal fat, triglycerides, and hyperglycemia. Hyperinsulinemia was insufficient to maintain normoglycemia, and beta cell mass and glucagon-like peptide 1 decreased over time in HFD and control animals. Despite lacking significant lipid abnormalities, nonalcoholic fatty liver disease was evident by 39 weeks. Our HFD model demonstrated that significant metabolic abnormalities may go undetected by current standard screening such as weighing and biochemistry.
- Published
- 2011
35. Fetal and Neonatal Exposure to Nicotine Disrupts Postnatal Lung Development in Rats: Role of VEGF and Its Receptors
- Author
-
Maria A. Petre, Alison C. Holloway, Jim Petrik, Mark D. Inman, Russ Ellis, and N. Renée Labiris
- Subjects
Male ,Vascular Endothelial Growth Factor A ,Nicotine ,medicine.medical_specialty ,Offspring ,medicine.medical_treatment ,Toxicology ,Article ,Fetus ,Pregnancy ,Internal medicine ,medicine ,Animals ,Weaning ,Rats, Wistar ,Lung ,Perinatal Exposure ,business.industry ,respiratory system ,medicine.disease ,Rats ,Receptors, Vascular Endothelial Growth Factor ,Endocrinology ,medicine.anatomical_structure ,Animals, Newborn ,Prenatal Exposure Delayed Effects ,Smoking cessation ,Female ,business ,Signal Transduction ,medicine.drug - Abstract
Many women are unable to quit smoking during pregnancy and therefore are prescribed drugs, including nicotine (nicotine replacement therapy [NRT]), to aid with smoking cessation. However, the consequences to the offspring of pregnant NRT users have not been well studied. The goals of this study were to determine the consequences of fetal and neonatal exposure to nicotine on lung development and function. Female rats were exposed to nicotine for 2 weeks prior to mating until weaning. Lungs were collected from saline and nicotine-treated rats from birth to adulthood to assess postnatal lung structure and function. Although nicotine exposure altered alveolarization at weaning, an effect that resolved by adulthood, it did not affect lung function at any of the ages investigated. However, nicotine exposure significantly decreased lung vascularization. The current study suggests that perinatal exposure to nicotine alters lung development, an effect which may be mediated via decreased vascular endothelial growth factor (VEGF) signaling.
- Published
- 2011
36. Effects in Rats of Maternal Exposure to Raspberry Leaf and Its Constituents on the Activity of Cytochrome P450 Enzymes in the Offspring
- Author
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Denis J. Crankshaw, Alison C. Holloway, Emilija Makaji, and Shirley Ho
- Subjects
Male ,medicine.medical_specialty ,Offspring ,Toxicology ,chemistry.chemical_compound ,Sex Factors ,Cytochrome P-450 Enzyme System ,Ellagic Acid ,Biotransformation ,Internal medicine ,medicine ,Animals ,Weaning ,Kaempferols ,Rats, Wistar ,Rosaceae ,biology ,Age Factors ,Cytochrome P450 ,Red raspberry leaf ,Rats ,Plant Leaves ,Endocrinology ,Liver ,Biochemistry ,chemistry ,Maternal Exposure ,biology.protein ,Female ,Quercetin ,Kaempferol ,Ellagic acid - Abstract
The goal of our study was to determine whether maternal exposure to red raspberry leaf (RRL) and its constituents can permanently alter biotransformation of fluorogenic substrates by cytochrome P450 (CYP) in the livers of male and female offspring. Nulliparous female rats received vehicle, raspberry leaf, kaempferol, quercetin, or ellagic acid orally once breeding had been confirmed until parturition. Hepatic microsomes were prepared from animals at birth (postnatal day 1 [PND1]), weaning (PND21), PND65, and PND120 to determine the biotransformation of 8 fluorogenic substrates. The pattern of biotransformation of all but 2 of the substrates was gender specific. Maternal consumption of RRL increased biotransformation of 3 substrates by female offspring at PND120 resulting in a more masculine profile. Kaempferol and quercetin had a similar effect to RRL. These results suggest that maternal consumption of either RRL or some of its constituents leads to long-term alterations of CYP activity in female offspring.
- Published
- 2010
37. Interleukin-15 Contributes to the Regulation of Murine Adipose Tissue and Human Adipocytes
- Author
-
Carl D. Richards, Ali A. Ashkar, Alison C. Holloway, Sarah Reid, Nicole G. Barra, Bernardo L. Trigatti, Randy Mackenzie, and Geoff H. Werstuck
- Subjects
medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Adipose tissue macrophages ,media_common.quotation_subject ,Appetite ,Mice, Obese ,Medicine (miscellaneous) ,Adipose tissue ,White adipose tissue ,Weight Gain ,Fat pad ,Proinflammatory cytokine ,Mice ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,Adipocyte ,Weight Loss ,Adipocytes ,medicine ,Animals ,Humans ,Obesity ,media_common ,Interleukin-15 ,Mice, Knockout ,Nutrition and Dietetics ,business.industry ,Lipid Metabolism ,Recombinant Proteins ,Killer Cells, Natural ,Mice, Inbred C57BL ,Adipose Tissue ,chemistry ,Cytokines ,Female ,Inflammation Mediators ,medicine.symptom ,Energy Intake ,business ,Weight gain - Abstract
An alarming global rise in the prevalence of obesity and its contribution to the development of chronic diseases is a serious health concern. Recently, obesity has been described as a chronic low-grade inflammatory condition, influenced by both adipose tissue and immune cells suggesting proinflammatory cytokines may play a role in its etiology. Here we examined the effects of interleukin-15 (IL-15) on adipose tissue and its association with obesity. Over expression of IL-15 (IL-15tg) was associated with lean body condition whereas lack of IL-15 (IL-15(-/-)) results in significant increase in weight gain without altering appetite. Interestingly, there were no differences in proinflammatory cytokines such as IL-6 and tumor necrosis factor-alpha (TNF-alpha) in serum between the three strains of mice. In addition, there were significant numbers of natural killer (NK) cells in fat tissues from IL-15tg and B6 compared to IL-15(-/-) mice. IL-15 treatment results in significant weight loss in IL-15(-/-) knockout and diet-induced obese mice independent of food intake. Fat pad cross-sections show decreased pad size with over expression of IL-15 is due to adipocyte shrinkage. IL-15 induces weight loss without altering food consumption by affecting lipid deposition in adipocytes. Treatment of differentiated human adipocytes with recombinant human IL-15 protein resulted in decreased lipid deposition. In addition, obese patients had significantly lower serum IL-15 levels when compared to normal weight individuals. These results clearly suggest that IL-15 may be involved in adipose tissue regulation and linked to obesity.
- Published
- 2010
38. Local Delivery of Nicotine does not Mitigate Fibrosis but may Lead to Angiogenesis
- Author
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Kenneth K. Ng, Michael A. Brook, Heather Sheardown, Alison C. Holloway, and Neven Awad
- Subjects
Nicotine ,Pathology ,medicine.medical_specialty ,Surface Properties ,Breast Implants ,Biomedical Engineering ,Biocompatible Materials ,Biomaterials ,chemistry.chemical_compound ,Mammary Glands, Animal ,Fibrosis ,Implant Capsular Contracture ,Materials Testing ,Animals ,Humans ,Medicine ,Rats, Wistar ,Drug Implants ,Wound Healing ,Neovascularization, Pathologic ,business.industry ,Capsule ,Capsular contracture ,medicine.disease ,Rats ,Nicotinic agonist ,chemistry ,Anesthesia ,Models, Animal ,Silicone Elastomers ,Female ,Implant ,business ,Wound healing ,Cotinine ,medicine.drug - Abstract
As with most implanted biomaterials, the wound healing response following implantation of a silicone breast implant leads to the formation of a fibrotic capsule. This can result in capsular contracture, a painful complication that often necessitates the removal of implant. It is well established that nicotine and nicotinic agonists inhibit inflammatory signaling. Based on the link between the inflammatory response and capsule formation, we hypothesized that local delivery of nicotine from the implant may lead to the reduction in inflammation and capsule thickness, which may ultimately reduce the incidence of capsular contracture. Nicotine was loaded into PDMS membranes using a previously established method. The loaded materials were implanted into the submammary pockets between the third and fourth mammary glands of rats. To confirm that the nicotine was acting locally and not systemically, serum cotinine, the primary metabolite of nicotine, was measured by ELISA at 3 days. Thirty days post implantation, the animals were euthanized and the tissue samples were fixed for histological analysis. Blood vessel density was measured immunohistochemically, while the capsule thickness was evaluated microscopically. While the presence of the nicotine metabolite, cotinine, in the serum at the early time points demonstrated that the nicotine was released locally from the devices, there were no significant differences in the capsule thickness between the control and experimental implants. However, the results indicated that there were differences in angiogenesis with the local delivery of nicotine, which may have other implications for the development of biomaterials.
- Published
- 2010
39. Effects of Cytochrome P450 Inhibitors on the Biotransformation of Fluorogenic Substrates by Adult Male Rat Liver Microsomes and cDNA-Expressed Rat Cytochrome P450 Isoforms
- Author
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Pamela Shen, Cristina S. Trambitas, Emilija Makaji, Alison C. Holloway, and Denis J. Crankshaw
- Subjects
Male ,DNA, Complementary ,Biology ,Toxicology ,Sulfaphenazole ,Biotransformation ,Coumarins ,Complementary DNA ,medicine ,Animals ,Humans ,heterocyclic compounds ,Enzyme Inhibitors ,Cytochrome P-450 Enzyme Inhibitors ,Fluorescent Dyes ,Cytochrome P450 ,CYP2E1 ,Rats ,Biochemistry ,Chlorzoxazone ,Microsomes, Liver ,Quinolines ,Microsome ,biology.protein ,Aryl Hydrocarbon Hydroxylases ,medicine.drug - Abstract
We have evaluated the use of a panel of six fluorogenic cytochrome P450 (CYP) substrates as a potential tool for rapid screening for global changes in CYP activity in rats under different physiological conditions. The biotransformation of 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin (AMMC), 7-benzyloxy-4-(trifluoromethyl)-coumarin, 7-benzyloxyquinoline, 3-cyano-7-ethoxycoumarin, 7-methoxy-4-(trifluoromethyl)-coumarin, and 7-ethoxy-4-trifluoromethyl-coumarin by microsomes from adult male rat liver were characterized, their sensitivities to 15 putative inhibitors were determined and compared to similar experiments using nine different complementary DNA (cDNA)-expressed rat CYPs. Inhibitory profiles of the substrates in microsomes were different from each other, with some overlap, suggesting that each substrate is to some extent biotransformed by a different CYP isoform. Ketoconazole and clotrimazole were nonselective inhibitors, while ticlopidine selectively inhibited biotransformation of AMMC. CYP2A1 did not biotransform any of the substrates, and CYP2E1 was insensitive to all the inhibitors tested. Some inhibitors did not affect the biotransformation of the fluorogenic substrates by cDNA-expressed isoforms as predicted by their effects on conventional substrates, e.g., chlorzoxazone and diethyldithiocarbamate were inactive against CYP2E1, and CYP2C6 was not inhibited by sulfaphenazole. When results in microsomes and cDNA-expressed CYPs were compared, only the majority of the biotransformation of AMMC by microsomes could be assigned with full confidence to a specific CYP isoform, namely CYP2D2. Nevertheless, different inhibitory profiles of the substrates indicate that the panel will be useful for rapid functional quantification of global CYP activity in rats under different experimental conditions. Our results also demonstrate the inappropriateness of extrapolating inhibitory data between conventional and fluorogenic CYP substrates.
- Published
- 2009
40. Effect of Nicotine Exposure During Pregnancy and Lactation on Maternal, Fetal, and Postnatal Rat IGF-II Profile
- Author
-
Michael Bell, Maria A. Petre, Alison C. Holloway, Qing Qiu, Andrée Gruslin, and Carolyn E. Cesta
- Subjects
Nicotine ,medicine.medical_specialty ,Gestational Age ,Fetal Development ,Insulin-Like Growth Factor II ,Pregnancy ,Lactation ,Internal medicine ,medicine ,Animals ,Nicotinic Agonists ,Rats, Wistar ,Fetus ,Fetal Growth Retardation ,business.industry ,Obstetrics and Gynecology ,Fetal Body Weight ,medicine.disease ,Adaptation, Physiological ,Rats ,Disease Models, Animal ,Low birth weight ,medicine.anatomical_structure ,Endocrinology ,Animals, Newborn ,In utero ,Prenatal Exposure Delayed Effects ,Gestation ,Female ,medicine.symptom ,business ,medicine.drug - Abstract
Smoking during pregnancy has been shown to result in an increased risk of low birth weight. However, the mechanisms underlying this association are poorly understood. The insulin-like growth factor (IGF) system plays a critical role in the regulation of feto-placental growth and development, and abnormal processing of proIGF-II may alter its biological function. Our goal was to investigate the effects of exposure to nicotine on maternal, fetal, and neonatal IGF-II processing. Nulliparous female Wistar rats were randomly assigned to receive saline (vehicle) or nicotine bitartrate (1 mg x kg(-1) x d(- 1)). After mating, dams were euthanized at embryonic days 15, 18, and 21, and fetal body weight was recorded. Serum (fetal and maternal) was collected for determination of the IGF-II profile by Western blot analysis. Nicotine exposure prevented the decrease in maternal IGF-II processing seen in controls with advancing gestation. However, there was no influence of nicotine on fetal levels of IGF-II. Postnatally (postnatal day [PND] 21), pups exposed to nicotine in utero had decreased levels of big IGF-II. Our results show, for the first time, that nicotine exposure prevents the decrease of IGF-II processing in the maternal compartment. This may represent a compensatory mechanism allowing the mother to counteract the negative influence of nicotine on fetal growth and development. Our postnatal findings of suppressed IGF-II may help explain some of the long-term health complications seen in individuals exposed to smoking in utero.
- Published
- 2009
41. Chronic Nicotine Blunts Hypoxic Sensitivity in Perinatal Rat Adrenal Chromaffin Cells via Upregulation of KATPChannels: Role of α7 Nicotinic Acetylcholine Receptor and Hypoxia-Inducible Factor-2α
- Author
-
Colin A. Nurse, Stephen Brown, Alison C. Holloway, and Josef Buttigieg
- Subjects
Nicotine ,medicine.medical_specialty ,Patch-Clamp Techniques ,alpha7 Nicotinic Acetylcholine Receptor ,Chromaffin Cells ,Receptors, Nicotinic ,Biology ,Membrane Potentials ,Catecholamines ,Pregnancy ,Ca2+/calmodulin-dependent protein kinase ,Internal medicine ,Adrenal Glands ,Glyburide ,Basic Helix-Loop-Helix Transcription Factors ,Electrochemistry ,medicine ,Animals ,Drug Interactions ,Nicotinic Agonists ,Enzyme Inhibitors ,Potassium Channels, Inwardly Rectifying ,Rats, Wistar ,Protein kinase A ,Cells, Cultured ,Protein Kinase C ,Protein kinase C ,Acetylcholine receptor ,Analysis of Variance ,General Neuroscience ,Depolarization ,Articles ,Sudden infant death syndrome ,Calcium Channel Blockers ,Cell Hypoxia ,Rats ,Up-Regulation ,Endocrinology ,Nicotinic agonist ,Animals, Newborn ,Calcium ,Female ,Peptides ,Cadmium ,medicine.drug - Abstract
Fetal nicotine exposure blunts hypoxia-induced catecholamine secretion from neonatal adrenomedullary chromaffin cells (AMCs), providing a link between maternal smoking, abnormal arousal responses, and risk of sudden infant death syndrome. Here, we show that the mechanism is attributable to upregulation of KATPchannels via stimulation of α7 nicotinic ACh receptors (AChRs). These KATPchannels open during hypoxia, thereby suppressing membrane excitability. Afterin uteroexposure to chronic nicotine, neonatal AMCs show a blunted hypoxic sensitivity as determined by inhibition of outward K+current, membrane depolarization, rise in cytosolic Ca2+, and catecholamine secretion. However, hypoxic sensitivity could be unmasked in nicotine-exposed AMCs when glibenclamide, a blocker of KATPchannels, was present. Both KATPcurrent density and KATPchannel subunit (Kir 6.2) expression were significantly enhanced in nicotine-exposed cells relative to controls. The entire sequence could be reproduced in culture by exposing neonatal rat AMCs or immortalized fetal chromaffin (MAH) cells to nicotine for ∼1 week, and was prevented by coincubation with selective blockers of α7 nicotinic AChRs. Additionally, coincubation with inhibitors of protein kinase C and CaM kinase, but not protein kinase A, prevented the effects of chronic nicotinein vitro. Interestingly, chronic nicotine failed to blunt hypoxia-evoked responses in MAH cells bearing short hairpin knockdown (>90%) of the transcription factor, hypoxia-inducible factor-2α (HIF-2α), suggesting involvement of the HIF pathway. The therapeutic potential of KATPchannel blockers was validated in experiments in which hypoxia-induced neonatal mortality in nicotine-exposed pups was significantly reduced after pretreatment with glibenclamide.
- Published
- 2009
42. Effect of Maternal Raspberry Leaf Consumption in Rats on Pregnancy Outcome and the Fertility of the Female Offspring
- Author
-
Alison C. Holloway, Shirley Ho, Jill R. Johnson, Denis J. Crankshaw, Boya Xiong, and Emilija Makaji
- Subjects
Infertility ,medicine.medical_specialty ,Offspring ,media_common.quotation_subject ,Reproductive medicine ,Fertility ,Biology ,Abortion ,Pregnancy ,medicine ,Animals ,Rats, Wistar ,Maternal-Fetal Exchange ,Rosaceae ,media_common ,Consumption (economics) ,Obstetrics ,Pregnancy Outcome ,Obstetrics and Gynecology ,medicine.disease ,Rats ,Plant Leaves ,Animals, Newborn ,Maternal Exposure ,Gestation ,Female ,Infertility, Female - Abstract
The use of herbal medicines by pregnant women is on the rise. However, there is limited information regarding the safety of these compounds during pregnancy. Therefore, the goal of this study was to explore the consequences of raspberry leaf use during gestation in Wistar rats.Female rats were randomly assigned to receive vehicle, raspberry leaf, or specific flavonoids in raspberry leaf (kaempferol or quercetin; 10 mg/kg per day) orally once breeding had been confirmed until parturition. We assessed pregnancy outcomes in the P generation and reproductive development/fertility in the F1 raspberry leaf-exposed female offspring.Raspberry leaf use during pregnancy was associated with increased gestation length and accelerated reproductive development in the F1 offspring.Results from this study have shown for the first time that raspberry leaf use during pregnancy can have long-term consequences for the health of the offspring and raise concerns about the safety of this herbal preparation for use during pregnancy.
- Published
- 2009
43. Developmental and lactational exposure to environmentally relevant concentrations of dieldrin does not alter pregnancy outcome and mammary gland morphology in BALB/c mice
- Author
-
Pezhman Mirshokraei, Alison C. Holloway, Warren G. Foster, and Bingjun Zhang
- Subjects
medicine.medical_specialty ,Chromatography, Gas ,Mammary gland ,Physiology ,Biology ,Biochemistry ,BALB/c ,Mice ,Dieldrin ,chemistry.chemical_compound ,Mammary Glands, Animal ,Pregnancy ,Lactation ,Internal medicine ,medicine ,Animals ,Sexual maturity ,Pesticides ,General Environmental Science ,Mice, Inbred BALB C ,Pregnancy Outcome ,Environmental Exposure ,biology.organism_classification ,medicine.disease ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Maternal Exposure ,Toxicity ,Female ,Breast feeding - Abstract
The objectives of this study were to: (1) determine the dosing range necessary to produce serum levels of dieldrin in mice representative of human body burdens; and (2) define the effect of developmental exposure to environmentally relevant concentrations of dieldrin on mammary gland development. Sexually mature female BALB/c mice (n=140) were randomly assigned to receive vehicle, 0.45, 2.25, 4.5, and 22.5 microg dieldrin/g body weight (BW)/day. Serum levels of dieldrin were quantified by gas chromatography in pooled samples (n=4/treatment group). Target levels of 10-30 ng/ml were achieved in 0.45 and 2.25 microg/g dose groups by the end of 2 weeks of treatment. Vehicle or dieldrin (0.45, 2.25, and 4.5 microg/g BW) was administered weekly to sexually mature female BALB/c mice (n=48) throughout mating, pregnancy, and lactation. Treatments had no effect on fertility parameters in dams or mammary gland morphology at sexual maturity. Developmental exposure to dieldrin has no effect on mammary gland development in aged BALB/c mice.
- Published
- 2008
44. Effects of fetal and neonatal exposure to nicotine on blood pressure and perivascular adipose tissue function in adult life
- Author
-
Yu-Jing Gao, Li-Ying Su, Alison C. Holloway, Robert M.K.W. Lee, Chao Lu, and Kumiko Takemori
- Subjects
Nicotine ,medicine.medical_specialty ,Offspring ,Adipose tissue ,Hemodynamics ,Aorta, Thoracic ,Blood Pressure ,Kidney ,Rats, Inbred WKY ,Fetus ,Pregnancy ,Internal medicine ,medicine.artery ,Animals ,Medicine ,Mesenteric arteries ,Pharmacology ,Aorta ,Dose-Response Relationship, Drug ,business.industry ,Anatomy ,Rats ,medicine.anatomical_structure ,Blood pressure ,Endocrinology ,Adipose Tissue ,Animals, Newborn ,Vasoconstriction ,Prenatal Exposure Delayed Effects ,Circulatory system ,Female ,business ,Blood vessel - Abstract
In Wistar rats, maternal exposure to nicotine was shown to impair the inhibitory function of perivascular adipose tissue on vascular contractility in the aorta of the offspring. It is not known whether an impairment of perivascular adipose tissue function occurs in smaller arteries, and whether the control of blood pressure is affected. Here we studied the blood pressure effects and the alteration of perivascular adipose tissue function in mesenteric arteries of the offspring born to Wistar-Kyoto rat (WKY) dams exposed to nicotine. Nulliparous female WKY rats were given either nicotine bitartrate (1 mg/kg/day) or saline (vehicle) by subcutaneous injection 2 weeks prior to mating, during pregnancy and until weaning. Blood pressure of the offspring and functional studies with mesenteric arteries were conducted. Tissue samples (thoracic aorta, mesenteric arteries, and kidneys) were collected for morphological and immunohistochemical examinations. Blood pressure increased from 14 weeks of age onwards in the offspring born to nicotine-exposed dams. Nicotine-exposed offspring showed a significant increase in the number of brown adipocytes in aortic perivascular adipose tissue relative to control offspring. In mesenteric arteries from control offspring, contractile responses induced by phenylephrine, serotonin, and 9,11-dideoxy-11alpha, 9alpha-epoxymethanoprostaglandin F(2)alpha (U44619) were significantly attenuated in the presence of perivascular adipose tissue, an effect not observed in the nicotine-exposed tissues. Endothelium-dependent relaxation responses to carbachol, kidney weight, the total number of nephrons and glomerulus' size were comparable in nicotine and saline groups. We conclude that fetal and neonatal exposure to nicotine caused blood pressure elevation. Alterations in perivascular adipose tissue composition and modulatory function are some of the mechanisms associated with this blood pressure increase.
- Published
- 2008
45. Follicle growth is inhibited by benzo-[a]-pyrene, at concentrations representative of human exposure, in an isolated rat follicle culture assay
- Author
-
Alison C. Holloway, Michael S. Neal, Jiping Zhu, and Warren G. Foster
- Subjects
Adult ,medicine.medical_specialty ,Fertilization in Vitro ,Gas Chromatography-Mass Spectrometry ,Follicle ,chemistry.chemical_compound ,Ovarian Follicle ,Internal medicine ,Benzo(a)pyrene ,medicine ,Animals ,Humans ,Sidestream smoke ,Ovarian follicle ,Cells, Cultured ,Ovary ,Smoking ,Rehabilitation ,Obstetrics and Gynecology ,Hair follicle ,Follicular fluid ,Rats ,Pregnancy rate ,Fertility ,Treatment Outcome ,medicine.anatomical_structure ,Endocrinology ,Reproductive Medicine ,chemistry ,Female ,Folliculogenesis - Abstract
The adverse effects of cigarette smoking on human fertility have been well documented. However, the mechanism(s) underlying the detrimental effects of cigarette smoking are unknown. Using a novel isolated rat follicle culture assay, we tested the hypothesis that benzo-[a]-pyrene (B[a]P), a constituent of cigarette smoke, can inhibit follicle growth.B[a]P levels were quantified in the serum and follicular fluid (FF) of women undergoing in vitro fertilization (IVF) treatment exposed to mainstream smoke (n = 19) and non-smokers (n = 10) by gas chromatography mass spectrometry. Isolated rat follicles were cultured with increasing concentrations of B[a]P (1.5-300 ng ml(-1)) and follicle diameter was measured daily.Mean ( +/- Standard error of the mean) B[a]P) was quantified in the serum (0.40 +/- 0.13 ng ml(-1)) and FF (1.32 +/- 0.68 ng ml(-1)) of women who smoke. IVF stimulation and outcome measures were similar between female smokers and non-smokers with the exception of implantation rate and pregnancy rate, which were both significantly lower (P0.05) in the MS group. B[a]P treatment significantly reduced rat follicle diameter and attenuated FSH stimulated growth in a dose-dependent manner, beginning at 1.5 ng ml(-1).Our data suggest that B[a]P, at levels representative of those measured in human FF, may adversely affect follicle development and be an ovarian toxicant.
- Published
- 2007
46. Perinatal Administration of a Selective Serotonin Reuptake Inhibitor Induces Impairments in Reproductive Function and Follicular Dynamics in Female Rat Offspring
- Author
-
Jim Petrik, Alison C. Holloway, Caroline J. Moore, Kaitlyn A. Chan, N. E. DeLong, and Deborah M. Sloboda
- Subjects
medicine.medical_specialty ,animal structures ,Offspring ,Serotonin reuptake inhibitor ,Reproductive medicine ,CLOCK Proteins ,Ovary ,Apoptosis ,Weaning ,Biology ,Fluoxetine Hydrochloride ,Estrus ,Ovarian Follicle ,Pregnancy ,Internal medicine ,Fluoxetine ,Follicular phase ,medicine ,Animals ,RNA, Messenger ,Rats, Wistar ,Estrous cycle ,Reproductive function ,Reproduction ,Age Factors ,Obstetrics and Gynecology ,Gene Expression Regulation, Developmental ,Endocrinology ,medicine.anatomical_structure ,Phenotype ,Animals, Newborn ,Maternal Exposure ,Prenatal Exposure Delayed Effects ,Female ,Selective Serotonin Reuptake Inhibitors ,Signal Transduction - Abstract
Up to 10% of pregnant women take antidepressants, of which selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed. Using a rodent model, we investigated the reproductive impacts of perinatal SSRI treatment on reproductive cyclicity and function in female offspring.Virgin Wistar rats were given oral vehicle (n = 10) or fluoxetine hydrochloride (FLX, 10 mg/kg/d; n = 11) from 2 weeks prior to mating until weaning. Pubertal onset and reproductive cyclicity in offspring were assessed. Blood and ovarian tissues were collected for measures of reproductive function.Perinatal FLX tends to induce irregular reproductive cycles in adult offspring, which most commonly manifest as a prolonged estrus phase (FLX 34% vs control [CON] 10%) relative to CON offspring. The FLX offspring tended to have longer cycles (P = .052), had more secondary follicles (P = .0067), more total follicles (P = .0310), and increased apoptotic ovarian cells (P.001). Prenatally exposed FLX offspring demonstrated elevated ovarian messenger RNA (mRNA) levels of ERβ (P = .008), Cry1 (P = .043), and tryptophan hydroxylase 2 (P = .024), independent of stage of cycle. Ovarian mRNA levels of brain and muscle Arnt-like protein 1 (P = .046) and Pet-1 (P = .021) were increased in FLX offspring a manner that was reproductive cycle stage dependent.This is the first study to investigate the postnatal effects of maternal perinatal exposure to FLX on adult offspring reproduction. We show that genes that regulate serotonin signaling and action in the ovary are altered in prenatally FLX-exposed offspring, which when coupled with increased expression of components of the core Circadian Locomotor Output Cycles Kaput (CLOCK) gene regulatory loop may suggest an interaction between serotonergic signaling and clock gene signaling pathways leading to the altered reproductive phenotype.
- Published
- 2015
47. Fetal Exposure to Sertraline Hydrochloride Impairs Pancreatic β-Cell Development
- Author
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Nicole E. De Long, Marie K. Gutgesell, Alison C. Holloway, and Jim Petrik
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Offspring ,Birth weight ,Serotonin reuptake inhibitor ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Pregnancy ,Internal medicine ,Insulin-Secreting Cells ,Sertraline ,medicine ,Animals ,Birth Weight ,Rats, Wistar ,geography ,geography.geographical_feature_category ,business.industry ,Pregnancy Outcome ,medicine.disease ,Islet ,Sertraline Hydrochloride ,Antidepressive Agents ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,Prenatal Exposure Delayed Effects ,Female ,Pancreas ,business ,030217 neurology & neurosurgery ,Selective Serotonin Reuptake Inhibitors ,medicine.drug - Abstract
Ten percent to 15% of women take selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy. Offspring exposed to SSRIs are more likely to have low birth weight; this is associated with an increased risk of development of diabetes in adulthood in part due to altered pancreatic development. The effects of perinatal exposure to SSRIs on pancreatic development are unknown. Therefore, the objective of this study was to determine the effect of fetal exposure to sertraline hydrochloride on pregnancy outcomes and pancreatic development. Wistar rats were given vehicle (n = 5) or sertraline hydrochloride (10 mg/kg/d; n = 8) via daily subcutaneous injection from the confirmation of mating until parturition. Results from this animal model demonstrated that offspring born to sertraline-exposed dams have no changes in birth weight but had a reduction in pancreatic β-cell area. The altered pancreatic islet development was a result of altered gene expression regulating islet development and survival. Therefore, fetal exposure to sertraline reduces β-cell capacity at birth, raising concerns regarding the long-term metabolic sequelae of such exposures.
- Published
- 2015
48. Maternal nicotine exposure leads to impaired disulfide bond formation and augmented endoplasmic reticulum stress in the rat placenta
- Author
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Catherine J. Nicholson, Alison C. Holloway, Michael K. Wong, and Daniel B. Hardy
- Subjects
medicine.medical_specialty ,Nicotine ,Science ,Placenta ,RNA Splicing ,Medical Physiology ,Protein Disulfide-Isomerases ,Apoptosis ,Regulatory Factor X Transcription Factors ,Placental insufficiency ,Biology ,fetal outcomes ,Pregnancy ,Internal medicine ,medicine ,Animals ,Amino Acids ,Protein disulfide-isomerase ,Hypoxia ,Fetus ,Multidisciplinary ,Endoplasmic reticulum ,Pharmacy and Pharmaceutical Sciences ,medicine.disease ,Endoplasmic Reticulum Stress ,Rats ,rats ,DNA-Binding Proteins ,Endocrinology ,medicine.anatomical_structure ,Gene Expression Regulation ,Maternal Exposure ,Unfolded protein response ,Unfolded Protein Response ,Medicine ,Female ,Signal transduction ,Oxidoreductases ,Biomarkers ,Transcription Factor CHOP ,nicotine ,medicine.drug ,Signal Transduction ,Transcription Factors ,Research Article - Abstract
Maternal nicotine exposure has been associated with many adverse fetal and placental outcomes. Although underlying mechanisms remain elusive, recent studies have identified that augmented endoplasmic reticulum (ER) stress is linked to placental insufficiency. Moreover, ER function depends on proper disulfide bond formation--a partially oxygen-dependent process mediated by protein disulfide isomerase (PDI) and ER oxidoreductases. Given that nicotine compromised placental development in the rat, and placental insufficiency has been associated with poor disulfide bond formation and ER stress, we hypothesized that maternal nicotine exposure leads to both placental ER stress and impaired disulfide bond formation. To test this hypothesis, female Wistar rats received daily subcutaneous injections of either saline (vehicle) or nicotine bitartrate (1 mg/kg) for 14 days prior to mating and during pregnancy. Placentas were harvested on embryonic day 15 for analysis. Protein and mRNA expression of markers involved in ER stress (e.g., phosphorylated eIF2α, Grp78, Atf4, and CHOP), disulfide bond formation (e.g., PDI, QSOX1, VKORC1), hypoxia (Hif1α), and amino acid deprivation (GCN2) were quantified via Western blot and/or Real-time PCR. Maternal nicotine exposure led to increased expression of Grp78, phosphorylated eIF2α, Atf4, and CHOP (p
- Published
- 2014
49. Chronic prenatal ethanol exposure alters expression of central and peripheral insulin signaling molecules in adult guinea pig offspring
- Author
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Daniel L. Mongillo, Christine C. Dobson, Andrew Winterborn, Alison C. Holloway, James F. Brien, James N. Reynolds, and Kersh Thevasundaram
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,Health (social science) ,Offspring ,medicine.medical_treatment ,Guinea Pigs ,Prefrontal Cortex ,Biology ,Toxicology ,Real-Time Polymerase Chain Reaction ,Biochemistry ,Receptor, IGF Type 2 ,Receptor, IGF Type 1 ,Behavioral Neuroscience ,Insulin-like growth factor ,Insulin-Like Growth Factor II ,Pregnancy ,Insulin receptor substrate ,Internal medicine ,medicine ,Animals ,Insulin-Like Growth Factor I ,Receptor ,2. Zero hunger ,Glucose tolerance test ,medicine.diagnostic_test ,Ethanol ,Insulin ,General Medicine ,medicine.disease ,Receptor, Insulin ,Insulin receptor ,Endocrinology ,Neurology ,Animals, Newborn ,Liver ,Prenatal Exposure Delayed Effects ,biology.protein ,Female ,Metabolic syndrome - Abstract
Maternal ethanol consumption during pregnancy can produce a range of teratogenic outcomes in offspring. The mechanism of ethanol teratogenicity is multi-faceted, but may involve alterations in insulin and insulin-like growth factor (IGF) signaling pathways. These pathways are not only important for metabolism, but are also critically involved in neuronal survival and plasticity, and they can be altered by chronic prenatal ethanol exposure (CPEE). The objective of this study was to test the hypothesis that CPEE alters expression of insulin and IGF signaling molecules in the prefrontal cortex and liver of adult guinea pig offspring. Pregnant Dunkin-Hartley-strain guinea pigs received ethanol (4 g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding (nutritional control) throughout gestation. Fasting blood glucose concentration was measured in male and female offspring at postnatal day 150-200, followed by euthanasia, collection of prefrontal cortex and liver, and RNA extraction. IGF-1, IGF-1 receptor (IGF-1R), IGF-2, IGF-2 receptor (IGF-2R), insulin receptor substrate (IRS)-1, IRS-2, and insulin receptor (INSR) mRNA expression levels were measured in tissues using quantitative real-time PCR. The mean maternal blood ethanol concentration was 281 ± 15 mg/dL at 1 h after the second divided dose of ethanol on GD 57. CPEE resulted in increased liver weight in adult offspring, but produced no difference in fasting blood glucose concentration compared with nutritional control. In the liver, CPEE decreased mRNA expression of IGF-1, IGF-1R, and IGF-2, and increased IRS-2 mRNA expression in male offspring only compared with nutritional control. Female CPEE offspring had decreased INSR hepatic mRNA expression compared with male CPEE offspring. In the prefrontal cortex, IRS-2 mRNA expression was increased in CPEE offspring compared with nutritional control. The data demonstrate that CPEE alters both central and peripheral expression of insulin and IGF signaling molecules at the mRNA level, which may be related to metabolic dysregulation in adult offspring. Furthermore, altered insulin and IGF signaling may be a mechanism of ethanol neurobehavioral teratogenicity.
- Published
- 2014
50. Fetal and neonatal exposure to nicotine in Wistar rats results in increased beta cell apoptosis at birth and postnatal endocrine and metabolic changes associated with type 2 diabetes
- Author
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Hertzel C. Gerstein, Jim Petrik, Alison C. Holloway, Gareth E. Lim, Warren G. Foster, and Katherine M. Morrison
- Subjects
Nicotine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Apoptosis ,Type 2 diabetes ,Biology ,Random Allocation ,Fetus ,Pregnancy ,Insulin-Secreting Cells ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Insulin ,Endocrine system ,Glucose homeostasis ,Obesity ,Rats, Wistar ,Adiposity ,Hemostasis ,Glucose tolerance test ,medicine.diagnostic_test ,Body Weight ,Glucose Tolerance Test ,medicine.disease ,Rats ,Disease Models, Animal ,Glucose ,Endocrinology ,Animals, Newborn ,Diabetes Mellitus, Type 2 ,Prenatal Exposure Delayed Effects ,Pregnancy, Animal ,Female ,medicine.drug - Abstract
Epidemiological studies report an increased risk of obesity and type 2 diabetes in children born to women who smoked during pregnancy. This study examines the effect of fetal and neonatal exposure to nicotine, the major addictive component of cigarettes, on postnatal growth, adiposity and glucose homeostasis.Female Wistar rats were given either saline (vehicle) or nicotine (1 mg kg(-1) day(-1)) during pregnancy and lactation. Serum and pancreas tissue were collected from the infant rats at birth. Postnatal growth was assessed weekly until the rats reached 26 weeks of age and glucose homeostasis was examined by OGTTs performed at 7 and 26 weeks of age.Exposure to nicotine resulted in increased postnatal growth and adiposity. Nicotine exposure also resulted in dysglycaemia at 7 and 26 weeks of age. Serum insulin concentrations were decreased in the pups exposed to nicotine at birth. This was associated with increased beta cell apoptosis (pups of saline-treated mothers 8.8+/-1.21% apoptotic beta cells; pups of nicotine-treated mothers 27.8+/-3.1% apoptotic beta cells).Fetal and neonatal exposure to nicotine results in metabolic changes in the offspring that are consistent with obesity and type 2 diabetes. We propose that these metabolic changes may be a consequence of the initial insult to the beta cell during fetal life and that this animal model has many characteristics of diabetes in humans.
- Published
- 2005
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