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This study aimed to investigate the mechanisms by which the association between maternal hyperglycemia and postnatal high-fat diet (HFD) exposure compromises metabolic parameters and hepatic autophagy in adult female pups. For this, Sprague Dawley rats, female pups from nondiabetic (control = FC) or diabetic (FD) mothers, were fed a standard diet (SD) or HFD from weaning until adulthood ( n minimum = 5 rats/group): FC/SD, FC/HFD, FD/SD, and FD/HFD. In adulthood, these rats were tested with the oral glucose tolerance test, euthanized, and serum biochemistry parameters were analyzed. Liver samples were collected to evaluate cytokines, redox status, and protein expression autophagy and apoptosis markers. Histomorphometric analyses and an assessment of lipofuscin accumulation were also performed to reflect incomplete autolysosomal digestion. The FC/HFD, FD/SD, and FD/HFD groups showed glucose intolerance and an increased number of hepatocytes. Furthermore, FD/SD and FD/HFD rats showed hyperlipidemia and insulin resistance. Adaptations in hepatic redox pathways were observed in the FD/SD group with increased antioxidant defense marker activity. The FD/SD group also exhibited increased autophagy protein expression, such as p-AMPK, LC3-II/LC3-I, and p62/SQSTM1, lipofuscin accumulation, and caspase-3 activation. After exposure to HFD, the adult female pups of diabetic rats had a reduced p-AMPK and LC3-II/LC3-I ratio, the presence of steatosis, oxidative stress, and inflammation. The reduction of autophagy, stimulated by HFD, may be of vital importance for the susceptibility to metabolic dysfunction-associated fatty liver disease induced by maternal diabetes.

This study investigated the late effects of maternal protein restriction (MPR) and early postnatal sugar consumption on liver health in male Sprague-Dawley rat offspring, focusing on changes observed throughout the aging process. The animals were divided into the following groups: Control (CTR): Male offspring whose dams consumed a normal protein diet (NPD, 17% protein) and water ad libitum during gestation and lactation, and then fed a NPD and water until PND 540; Control + Sugar (CTR + SUG): The same treatment as CTR, but consuming a sugar solution (10% diluted in water) from postnatal day (PND) 21-90, and then fed a NPD and water until PND 540; Gestational and Lactational Low Protein (GLLP): Male offspring whose dams consumed a low-protein diet (LPD, 6% protein) during gestation and lactation and, then fed a NPD and water ad libitum until PND 540; Gestational and Lactational Low Protein + Sugar (GLLP + SUG): male offspring whose dams consumed a LPD during gestation and lactation, and then fed a NPD and a sugar solution (10% diluted in water) ad libitum from PND 21 to 90. On PND 540, the animals were anesthetized, weighed, and euthanized, and their livers were collected for morphological and molecular analyses. The GLLP and GLLP + SUG groups showed lower body weight and lower retroperitoneal fat weight compared to the CTR and CTR + SUG groups. Morphological analysis revealed inflammatory foci in the liver from the CTR + SUG, GLLP, and GLLP + SUG groups, compared to the CTR group. Hepatic activities of CAT, SOD, and GSH-Px were increased in the GLLP + SUG group and decreased in the GLLP group, compared to the CTR group. Immunohistochemistry showed a significant increase in occupied area per foci de hepatocytes positive for GSTpi (placental form) in the CTR + SUG, GLLP, and GLLP + SUG groups, compared to the CTR group. Proteomic analysis of the groups revealed significant changes in hepatic metabolic and inflammatory pathways. In the CTR + SUG group, upregulated pathways associated with non-alcoholic fatty liver disease (NAFLD) and downregulated pathways related to autophagy were observed. In the GLLP and GLLP + SUG groups, there was a significant impact on metabolic pathways, including glucose metabolism, gluconeogenesis, glycogenesis, and cellular stress responses. An upregulation of pathways associated with chemokine- and cytokine-mediated inflammatory processes was also identified, indicating activation of the immune system in the liver during aging. Therefore, MPR, with or without postnatal sugar consumption, resulted in hepatic changes in metabolism and the antioxidant defense in old male offspring., Competing Interests: Declaration of Competing interest The authors declare no conflict of interest., (Copyright © 2025 Elsevier B.V. All rights reserved.)

We assess the effects of aerobic exercise on the soleus and plantaris muscles in adult rats submitted to maternal protein restriction (MPR) during pregnancy and lactation. Male offspring born from dams fed with control (17%-control) or low protein diets (6%-restricted) were randomly assigned to untrained or aerobic exercise, and morphological, biochemical, molecular, and proteomic analyses were performed. The proteome analysis showed many proteins involved with muscle energy metabolism, with emphasis on the glycolysis (ALDOA, ENO1, PGAM2, and TPI1) and glycogen (PYGM) pathways. MPR decreased ALDOA, TPI1, ENO1, PGAM2, and PYGM expression and increased glycogen content in Soleus (SOL); Plantaris (PL) increased PYGM, ALDOA, GAPDH, PKM, and TPI1 protein expression. Aerobic exercise (AE) normalized the glycemic index in restricted animals and increased the expression of proteins PYGM, ALDOA, ENO1, PGAM2, and TPI1, also decreasing glycogen content in the SOL. In the PL, aerobic exercise increased PYGM, ALDOA, GAPDH, PKM, and TPI1 proteins without a change in muscle glycogen content. Our study demonstrates that MPR and AE promoted differential muscle-specific adaptations, and aerobic exercise can represent a way to attenuate early muscle morphophysiological and metabolic changes in offspring rats submitted to MPR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Aim: To evaluate the repercussions of periodontitis and diabetes association on rat pregnancy and newborns., Methods: Diabetes was induced in female Wistar rats 24 h after birth through the administration of Streptozotocin. The diabetic condition of the rats was further confirmed in adulthood. After mating, the pregnant rats were distributed into four experimental groups (n = 12 rats/group): nondiabetic and diabetic with and without periodontitis. Periodontitis was induced by a ligature inserted into the first molar on day 0 of pregnancy. Body weight, water and feed consumption were evaluated weekly, and an oral glucose tolerance test was performed on day 17 of pregnancy. On day 21 of pregnancy, the animals were anesthetized and killed for organ removal. The hemimandibles were collected to analyze alveolar bone loss. Immunological and biochemical parameters were evaluated in the maternal blood samples, and reproductive performance was analyzed. The newborns were weighed, and anomalies evaluated., Results: The group with diabetes and periodontitis had a greater degree of alveolar bone loss, along with higher relative pancreatic weight, blood glucose levels, triglyceride and inflammatory cytokine levels, hepatic transaminase activity, and embryonic losses. In addition, these newborns had increased body weight, placental weight, a greater number of ossification centers, and a higher rate of visceral and skeletal anomalies., Conclusion: The combination of maternal diabetes and periodontitis negatively impacts maternal parameters and fetal development. The findings reinforce the importance of maintaining maternal oral health to ensure the general health of the offspring, especially in cases where diabetes is present., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Aims: To evaluate the cell proliferation and death, and structural morphology of the pancreatic islet cells of the rats with hyperglycemia in the first month of life and compare to those of the control rats., Main Methods: Female Sprague-Dawley newborn rats received Streptozotocin (a beta-cytotoxic drug) at birth for diabetes induction. Control and hyperglycemic animals were euthanized on different days of life: 5, 10, 15, and 30. The pancreas was collected and processed for immunohistochemical analysis of cleaved Caspase-3 (cell death), Ki-67 (cell proliferation), PDX-1 (transcription factor responsible for insulin synthesis), and endocrine hormones (insulin, glucagon, and somatostatin)., Key Findings: Control females showed a higher percentage (%) of Ki-67-positive( + ) cells on D10 and D15, a higher % of insulin + and somatostatin + cells on D15 and D30, a lower % of PDX-1 + cells on D10, and a higher % of glucagon + cells on D10 and D30. Hyperglycemic females showed a lower % of Ki-67 + cells on D15, a higher % of cleaved Caspase-3 + cells on D15, and insulin + cells on D15 and D30. In the comparison among the experimental groups, the hyperglycemic females showed an increased % of cleaved Caspase-3 + and Ki-67 + cells and a lower % of PDX-1 + cells., Significance: This study enabled a better understanding of the abnormal pancreas development regarding cellular proliferation, apoptosis, and hormonal synthesis in the neonatal period. Thus, the pancreatic islets of hyperglycemic rats do not reestablish the normal endocrine cell population, and cellular apoptosis overcame the proliferative activity of these cells., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study aims to evaluate the phytochemical properties of Bauhinia holophylla (Bong.) Steud leaf extract, and their impact on maternal reproductive and fetal development in diabetic rats. For this, adult female Wistar rats (100 days of life) received streptozotocin (40 mg/Kg, intraperitoneal) for induction of diabetes, were mated and distributed into four groups: Nondiabetic; Nondiabetic given B. holophylla; Diabetic; and Diabetic given B. holophylla. The plant extract was given by gavage at increasing doses: 200, 400, and 800 mg/Kg. At day 21 of pregnancy, liver and blood samples were obtained for oxidative parameters and biochemical analysis, respectively. The uterus was removed for maternal-fetal outcomes. Phytochemical analysis showed a high content of phenolic components and biogenic amines. B. holophylla extract did not alter the glycemic levels but improved the lipid profile in diabetic animals. Besides that, the number of live fetuses and maternal weight gain were decreased in Diabetic group, and were not observed in animals treated. The group Diabetic treated presented a higher percentage of fetuses classified as adequate for gestational age compared to the Diabetic group. However, the treatment with plant extract caused embryo losses, fetal growth restriction, and teratogenicity in nondiabetic rats. Thus, the indiscriminate consumption requires carefulness.

Maternal diabetes may influence glucose metabolism in adult offspring, an area with limited research on underlying mechanisms. Our study explored the impact of maternal hyperglycemia during pregnancy on insulin resistance development. Adult female Sprague-Dawley rats from control and diabetic mothers were mated, and their female offspring were monitored for 150 days. The rats were euthanized for blood and muscle samples. Maternal diabetes led to heightened insulin levels, increased HOMA-IR, elevated triglycerides, and a raised TyG index in adult offspring. Muscle samples showed a decreased protein expression of AMPK, PI3K, MAPK, DRP1, and MFF. These changes induced intergenerational metabolic programming in female pups, resulting in insulin resistance, dyslipidemia, and glucose intolerance by day 150. Findings highlight the offspring's adaptation to maternal hyperglycemia, involving insulin resistance, metabolic alterations, the downregulation of insulin signaling sensors, and disturbed mitochondrial morphology. Maintaining maternal glycemic control emerges as crucial in mitigating diabetes-associated disorders in adult offspring., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: To investigate the transgenerational effect of maternal hyperglycemia on oxidative stress markers, lipid profile, glycemia, pancreatic beta (β)-cells, and reproductive outcomes in the F2 adult generation. Additionally, to expand the knowledge on transgenerational diabetes the F3 generation at birth will be evaluated., Methods: On day 5 of postnatal life female Sprague-Dawley rat newborns (F0 generation) were distributed into two groups: Diabetic (Streptozotocin-STZ, 70 mg/kg body weight, subcutaneous route) and Control rats. Adult female rats from the F0 generation and subsequently the F1 generation were mated to obtain the F2 generation, which was distributed into F2 generation (granddaughters) from control (F2&#95;C) and diabetic (F2&#95;D) rats. Oral Glucose Tolerance Test (OGTT), the area under the curve (AUC), blood biochemical analyses, and pancreatic morphology were analyzed before pregnancy. Reproductive outcomes were performed at the end of pregnancy. At birth, the glycemia and body weight of F3&#95;C and F3&#95;D rats were determined. p < 0.05 was considered significant., Results: F2&#95;D had higher body weight, triglyceride levels, and percentage of insulin-immunostained cells, contributing to glucose intolerance, and insulin resistance before pregnancy. At day 21 of pregnancy, the F2&#95;D showed increased embryonic losses before and after implantation (84.33 and 83.74 %, respectively). At birth, F3&#95;D presented hyperglycemia, and 16.3 % of newborns were large for pregnancy age (LGA)., Conclusion: Diabetes induction since the neonatal period in the first generation (F0) led to transgenerational (F2 and F3 generations) changes via the maternal lineage of female rats, confirming the relevance of control strictly the glycemia all the time., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

We aimed to evaluate how high-fat diet consumption can interfere with rat reproductive performance and fetal development. High-fat diet (HFD) was initiated in 30-day-old rats, distributed into two groups (n=7 animals/group): Rats receiving a standard diet and rats receiving HFD. At adulthood, the rats were mated, and on day 21 of pregnancy, the females were anesthetized, decapitated, and submitted to laparotomy to obtain visceral and periovarian adipose tissue. The uterine horns were exposed for analysis of maternal reproductive performance. The fetuses and placentas were weighed and analyzed. Pearson's correlation test was used, and p<0.05 was considered significant. There was a significant positive correlation (HFD consumption x increased periovarian fat) and a negative correlation with the implantation, live fetus numbers and lower litter weight. Furthermore, the increased relative weight of periuterine fat was related to the lower number of live fetuses and litter weight. Regarding the fetal weight classification, there was a negative correlation between the relative weight of periovarian fat and the percentage of fetuses appropriate for gestational age and large for gestational age. Therefore, our findings show that HFD maternal intake negatively influenced on reproductive performance and fetal growth.

Maternal diabetes can influence the development of offspring during fetal life and postnatally. Curatella americana is a plant used as a menstrual cycle regulator and to prevent diabetes. This study evaluates the effects of C. americana aqueous extract on the estrous cycle and preimplantation embryos of adult female pups from diabetic rats. Female Sprague Dawley newborn rats received Streptozotocin or vehicle (citrate buffer). At adulthood, were submitted to the Oral Glucose Tolerance Test, and mated. The female rats were obtained and were distributed into four experimental groups: OC and OC/T represent female pups of control mothers and received water or plant extract, respectively; OD and OD/T represent female pups of diabetic mothers and received water or plant extract, respectively. The estrous cycle was followed for 10 days, the rats were mated and on gestational day 4 was performed preimplantation embryo analysis. Phenolic composition and biogenic amines in the extract were analyzed about the influence of the thermal process. The female pups from diabetic dams exhibited glucose intolerance, irregular estral cycle and a higher percentage of pre-embryos in delayed development (morula stage). After C. americana treatment, OD/T group no present a regular estrous cycle. Furthermore, the infusion process increases phenolic compounds and biogenic amines levels, which can have anti-estrogenic effect, anticipates the early embryonic development, and impair pre-implantation embryos. Thus, the indiscriminate use of medicinal plants should be avoided in any life phases by women, especially during pregnancy., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.)

Introduction: The effect of gestational age and fetal growth on the oxidant/antioxidant status of breast milk is poorly understood., Objective: To evaluate the oxidative stress biomarkers in colostrum and mature milk according to gestational age and fetal growth., Method: A longitudinal study with mothers of premature and term infants, born in a tertiary referral hospital between 2014-2018. Inclusion criteria: postpartum women with a singleton pregnancy, who intended to exclusively breastfeed. Exclusion criteria: maternal diabetes, use of medication, drug addiction, congenital infection or malformation, mastitis, and failure to collect colostrum. Four groups were formed according to gestational age and birth weight (appropriate and small): Preterm small ( n  = 37), Preterm appropriate ( n  = 99), Full-term small ( n  = 65), and Full-term appropriate (control, n  = 69). The colostrum samples were collected between 24-72 h and the mature milk was sampled in the 4th week of lactation for malondialdehyde (biomarker for lipid peroxidation) and Glutathione peroxidase, Catalase, and Superoxide dismutase measurements. The data were compared among groups using the Chi-square test or Fisher's exact test, one-way analysis of variance followed by Wald's Distribution test and repeated measures analysis of variance., Results: We found a lower malondialdehyde level in colostrum in preterm groups and term small for gestational age, and the antioxidant enzymes Superoxide dismutase and Catalase activities were higher for preterm compared to term groups. The malondialdehyde levels differed in mature milk samples (Full-term small > Full-term appropriate > Preterm small > Preterm appropriate). The malondialdehyde levels increased during lactation in all groups except Preterm appropriate, and the levels of Catalase decreased in preterm groups., Conclusion: The oxidative status in breast milk is influenced by gestational age and fetal growth, which increased antioxidant defense for preterm infants and decreased oxidative stimuli for small for gestational age infants. These findings contribute to encouraging breastfeeding for newborns.

We analyzed the influence of maternal hyperglycemia and the post-weaning consumption of a high-fat diet on the mitochondrial function and ovarian development of the adult pups of diabetic rats. Female rats received citrate buffer (Control-C) or Streptozotocin (for diabetes induction-D) on postnatal day 5. These adult rats were mated to obtain female pups (O) from control dams (OC) or from diabetic dams (OD), and they received a standard diet (SD) or high-fat diet (HFD) from weaning to adulthood and were distributed into OC/SD, OC/HFD, OD/SD, and OD/HFD. In adulthood, the OGTT and AUC were performed. These rats were anesthetized and euthanized for sample collection. A high percentage of diabetic rats were found to be in the OD/HFD group (OD/HFD 40% vs. OC/SD 0% p < 0.05). Progesterone concentrations were lower in the experimental groups (OC/HFD 0.40 ± 0.04; OD/SD 0.30 ± 0.03; OD/HFD 0.24 ± 0.04 vs. OC/SD 0.45 ± 0.03 p < 0.0001). There was a lower expression of MFF (OD/SD 0.34 ± 0.33; OD/HFD 0.29 ± 0.2 vs. OC/SD 1.0 ± 0.41 p = 0.0015) and MFN2 in the OD/SD and OD/HFD groups (OD/SD 0.41 ± 0.21; OD/HFD 0.77 ± 0.18 vs. OC/SD 1.0 ± 0.45 p = 0.0037). The number of follicles was lower in the OD/SD and OD/HFD groups. A lower staining intensity for SOD and Catalase and higher staining intensity for MDA were found in ovarian cells in the OC/HFD, OD/SD, and OD/HFD groups. Fetal programming was responsible for mitochondrial dysfunction, ovarian reserve loss, and oxidative stress; the association of maternal diabetes with an HFD was responsible for the higher occurrence of diabetes in female adult pups.

Diabetes mellitus increases the risk of obstetric complications, morbidity, and infant mortality. Controlled nutritional therapy with micronutrients has been employed. However, the effect of calcium (Ca 2+ ) supplementation on diabetic pregnancy is unclear. We aimed to evaluate whether diabetic rats supplemented with Ca 2+ during pregnancy present better glucose tolerance, redox status, embryonic and fetal development, newborn weight, and the prooxidant and antioxidant balance of male and female pups. For this, newborn rats received the beta-cytotoxic drug streptozotocin for inducing diabetes on the day of birth. In adulthood, these rats were mated and treated with Ca 2+ twice a day from day 0 to day 20 of pregnancy. On day 17, the pregnant rats were submitted to the oral glucose tolerance test (OGTT). At the end of pregnancy, they were anesthetized and killed to collect blood and pancreas samples. The uterine horns were exposed for an evaluation of maternal reproductive outcomes and embryofetal development, and the offspring's liver samples were collected for redox status measurement. Nondiabetic and diabetic rats supplemented with Ca 2+ showed no influence on glucose tolerance, redox status, insulin synthesis, serum calcium levels, and embryofetal losses. The reduced rate of newborns classified as adequate for gestational age (AGA) and higher rates of LGA (large) and small (LGA) newborns and higher -SH and GSH-Px antioxidant activities in female pups were observed in diabetic dams, regardless of supplementation. Thus, maternal supplementation caused no improvement in glucose tolerance, oxidative stress biomarkers, embryofetal growth and development, and antioxidants in pups from diabetic mothers., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

We used uncontrolled maternal diabetes as a model to provoke fetal growth restriction in the female in the first generation (F 1 ) and to evaluate reproductive outcomes and the possible changes in metabolic systems during pregnancy, as well as the repercussions at birth in the second generation (F 2 ). For this, nondiabetic and streptozotocin-induced severely diabetic Sprague-Dawley rats were mated to obtain female pups (F 1 ), which were classified as adequate (AGA) or small (SGA) for gestational weight. Afterward, we composed two groups: F 1 AGA from nondiabetic dams (Control) and F 1 SGA from severely diabetic dams (Restricted) (n minimum = 10 animals/groups). At adulthood, these rats were submitted to the oral glucose tolerance test, mated, and at day 17 of pregnancy, blood samples were collected to determine glucose and insulin levels for assessment of insulin resistance. At the end of the pregnancy, the blood and liver samples were collected to evaluate redox status markers, and reproductive, fetal, and placental outcomes were analyzed. Maternal diabetes was responsible for increased SGA rates and a lower percentage of AGA fetuses (F 1 generation). The restricted female pups from severely diabetic dams presented rapid neonatal catch-up growth, glucose intolerance, and insulin resistance status before and during pregnancy. At term pregnancy of F 1 generation, oxidative stress status was observed in the maternal liver and blood samples. In addition, their offspring (F 2 generation) had lower fetal weight and placental efficiency, regardless of gender, which caused fetal growth restriction and confirmed the fetal programming influence., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Ethnopharmacological Relevance: Plants and herbs have been used by women throughout history for therapeutic purposes. Strychnos pseudoquina, a plant used in the treatment of various diseases, can also function as an abortive herb. There is no scientific confirmation of its effects during pregnancy, and the activity of this plant needs to be substantiated or refuted with experimental evidence., Aim of the Study: Evaluating the effect of the S. pseudoquina aqueous extract on maternal reproductive toxicity and fetal development., Materials and Methods: The aqueous extract of S. pseudoquina bark was evaluated in Wistar rats. Pregnant rats were distributed into four experimental groups (n = 12 rats/group): Control = treated with water (vehicle); Treated 75, Treated 150, and Treated 300 = treated with S. pseudoquina at dose 75, 150 and 300 mg/kg, respectively. The rats were treated by an intragastric route (gavage) from day 0 to day 21 of pregnancy. At the end of pregnancy, maternal reproductive outcomes, organs, biochemical and hematological profiles, fetuses, and placentas were analyzed. Maternal toxicity was evaluated through body weight gain, water, and food intake. With knowledge of the harmful dosage of the plant, other rats were used on gestational day 4 for the evaluation of morphological analyses before embryo implantation. P < 0.05 was considered as statistically significant., Results: The S. pseudoquina treatment showed elevated liver enzymatic activities. The Treated 300 group presented toxicity with reduced maternal body weight, water and food intake, and increased kidney relative weight compared to those of the Control group. At a high dosage, the plant presents an abortifacient activity, confirmed by embryo losses before and after implantation and degenerated blastocysts. In addition, the treatment contributed to an increased percentage of fetal visceral anomalies, decreased ossification sites, and intrauterine growth restriction (300 mg/kg dose)., Conclusion: In general, our study showed that an aqueous extract of S. pseudoquina bark caused significant abortifacient activity that testified to its traditional use. Furthermore, the S. pseudoquina extract caused maternal toxicity that contributed to impaired embryofetal development. Therefore, the use of this plant should be completely avoided during pregnancy to prevent unintended abortion and risks to maternal-fetal health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This study aimed to evaluate the gold nanoparticles (AuNPs) animal sterilizing potential after intratesticular injections and long-term adverse reproductive and systemic effects. Adult male Wistar rats were divided into control and gold nanoparticle (AuNPs) groups. The rats received 200 µL of saline or AuNPs solution (16 µg/mL) on experimental days 1 and 7 (ED1 and ED7). After 150 days, the testicular blood flow was measured, and the rats were mated with females. After mating, male animals were euthanized for histological, cellular, and molecular evaluations. The female fertility indices and fetal development were also recorded. The results indicated increased blood flow in the testes of treated animals. Testes from treated rats had histological abnormalities, shorter seminiferous epithelia, and oxidative stress. Although the sperm concentration was lower in the AuNP-treated rats, there were no alterations in sperm morphology. Animals exposed to AuNPs had decreased male fertility indices, and their offspring had lighter and less efficient placentas. Additionally, the anogenital distance was longer in female fetuses. There were no changes in the histology of the kidney and liver, the lipid profile, and the serum levels of LH, testosterone, AST, ALT, ALP, albumin, and creatinine. The primary systemic effect was an increase in MDA levels in the liver and kidney, with only the liver experiencing an increase in CAT activity. In conclusion, AuNPs have a long-term impact on reproduction with very slight alterations in animal health. The development of reproductive biotechnologies that eliminate germ cells or treat local cancers can benefit from using AuNPs., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Evaluation of the possible toxic effects of occupational exposure to anesthetics is of great importance, and the literature is limited in assessing the possible association between occupational exposure to anesthetics and oxidative stress and genetic damage. To contribute to the gap of knowledge in relation to cause-effect, this cohort study was the first to monitor exposure assessment and to evaluate oxidative stress, DNA damage, and gene expression (OGG1, NRF2, HO-1, and TP53) in young adult physicians occupationally exposed to the most modern halogenated anesthetics (currently the commonly used inhalational anesthetics worldwide) in addition to nitrous oxide gas during the medical residency period. Therefore, the physicians were evaluated before the beginning of the medical residency (before the exposure to anesthetics-baseline), during (1 1/2 year) and at the end (2 1/2 years) of the medical residency. Anesthetic air monitoring was performed in operating rooms without adequate ventilation/scavenging systems, and biological samples were analyzed for lipid peroxidation, protein carbonyl content, primary and oxidative DNA damage, antioxidant enzymes and plasma antioxidant capacity, and expression of some key genes. The results showed induction of lipid peroxidation, DNA damage, glutathione peroxidase activity, and NRF2 and OGG1 expression up to the end of medical residency. Plasma antioxidant capacity progressively increased throughout medical residency; oxidative DNA damage levels started to increase during medical residency and were higher at the end of residency than at baseline. Protein carbonyls increased during but not at the end of medical residency compared to baseline. The antioxidant enzyme superoxide dismutase activity remained lower than baseline during and at the end of medical residency, and HO-1 (related to antioxidant defense) expression was downregulated at the end of medical residency. Additionally, anesthetic concentrations were above international recommendations. In conclusion, high concentrations of anesthetic in the workplace induce oxidative stress, gene expression modulation, and genotoxicity in physicians during their specialization period., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Morinda citrifolia L., also known as Noni, is widely used plant in folk medicine for various therapeutic purposes. However, reports on its effects during pregnancy are limited. Therefore, the objective of this study was to evaluate the effects of the M. citrifolia fruit extract on maternal performance and fetal development during pregnancy in rats. Pregnant Wistar rats (n = 12/group) were treated from gestational days (GD) 0-21 with water (control group) or the aqueous extract of M. citrifolia fruit at doses of 200, 400, or 750 mg/kg, orally. During pregnancy, clinical signs of toxicity, maternal weight, feed intake, and water consumption were noted. On GD 21, the rats were anesthetized and blood was collected to evaluate various biochemical parameters. During laparotomy, reproductive performance parameters were recorded, and fetuses were weighed and the anomalies analyzed. Reduced placental efficiency and fetal growth restriction were observed in the group treated with 400 mg/kg of M. citrifolia extract. The highest dose (750 mg/kg) augmented aspartate aminotransferase concentration and preimplantation losses, while reducing the number of live fetuses. Furthermore, both doses (400 and 750 mg/kg) of the plant extract caused fetal anomalies. In conclusion, consumption of high doses of the M. citrifolia aqueous extrac during pregnancy leads to maternal hepatotoxicity, anti-implantation effects, intrauterine growth restriction and fetal abnormalities, indicating that the plant fruit extract can be harmful to both the mother and the fetus.

Studies on vitamin D supplementation have been performed in experimental and clinical investigations considering gestational diabetes and/or vitamin D deficiency in pregnancy. However, the results are controversial and few present the effects and mechanisms of this micronutrient on pregestational diabetes. The objective of this study was to evaluate the effect of vitamin D on the pregnancy of rats with pre-existing diabetes and their fetuses. Pregestational diabetes was induced in Sprague-Dawley rats at birth. The adult diabetic and nondiabetic rats were orally administered with vitamin D (cholecalciferol) throughout the pregnancy. The diabetes status was monitored during pregnancy by an oral glucose tolerance test (OGTT). At the end of the pregnancy, pancreas and blood samples were collected for morphological analyses and lipid peroxidation measurements, respectively. The influence of vitamin D treatment on reproductive outcomes, fetal growth, and development were compared to those of untreated diabetic and nondiabetic pregnant rats. P < 0.05 was considered a significant statistical limit. The diabetic rats given vitamin D had a greater number of insulin-positive cells, contributing to reduced blood glucose levels and thiobarbituric acid reactive substance concentrations (TBARS-an indicator of membrane lipid peroxidation), and increased reduced thiol group levels, contributing to suitable intrauterine conditions for better fetal development, which was confirmed by higher fetal viability rates. Thus, this study shows the effects and mechanisms of vitamin D supplementation on pre-existing diabetes in pregnant rats, confirming its beneficial effects on maternal redox status and glycemic control, and the decline of adverse maternal-fetal repercussions., (© 2022. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Redox status assessments are time-consuming, require a large volume of samples and great reagent amounts, and are not adequately described for methodological reproducibility. Here, the objective was to standardize redox balance determination, based on previously described spectrophotometric tests in pregnant rats, to improve precision, time dispensed, and the volume of samples and reagents, while maintaining accuracy and adequate cost benefits. This protocol summarizes oxidative stress markers, which focus on spectrophotometric tests for the assessment of thiobarbituric acid-reactive substances, reduced thiol groups, and hydrogen peroxide, as well as the antioxidant activity of superoxide dismutase, glutathione peroxidase, and catalase in washed erythrocyte and serum samples from full-term pregnant rats. For non-pregnant rats and other species, it is necessary to standardize these determinations, especially the sample volume. All measurements were normalized by the estimated protein concentrations in each sample. To establish optimum conditions for the reproducibility of the proposed methods, we describe all changes made in each assay's steps based on the reference method reassessed for the new standardizations. Furthermore, the calculations of the concentrations or activities of each marker are presented. Thus, we demonstrate that the analysis of serum samples is easier and faster, but it is impossible to detect catalase activity. Furthermore, the proposed methods can be applied for redox balance determination, especially using smaller reagent amounts and lower sample volumes in lesser time without losing accuracy, as is required in obtaining samples during rat pregnancy., Competing Interests: Competing interests The authors have no competing interests to declare., (Copyright © 2023 The Authors; This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).)

Rosmarinus officinalis L. (rosemary) is an aromatic culinary herb. Native to the Mediterranean region, it is currently cultivated worldwide. In addition to its use as a condiment in food preparation and in teas, rosemary has been widely employed in folk medicine and cosmetics. Several beneficial effects have been described for rosemary, including antimicrobial and antioxidant activities. Here, we investigated the mechanisms accounting for the antioxidant activity of the glycolic extract of R. officinalis ( Ro ) in isolated rat liver mitochondria (RLM) under oxidative stress conditions. We also investigated its protective effect against acetaminophen-induced hepatotoxicity in vivo. A crude extract was obtained by fractionated percolation, using propylene glycol as a solvent due to its polarity and cosmeceutical compatibility. The quantification of substances with recognized antioxidant action revealed the presence of phenols and flavonoids. Dereplication studies carried out through LC-MS/MS and GC-MS, supported by The Global Natural Product Social Molecular Networking (GNPS) platform, annotated several phenolic compounds, confirming the previous observation. In accordance, Ro decreased the production of reactive oxygen species (ROS) elicited by Fe 2+ or t -BOOH and inhibited the lipid peroxidation of mitochondrial membranes in a concentration-dependent manner in RLM. Such an effect was also observed in liposomes as membrane models. Ro also prevented the oxidation of mitochondrial protein thiol groups and reduced glutathione (GSH). In model systems, Ro exhibited a potent scavenger activity toward 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radicals and superoxide anions. It also demonstrated an Fe 2+ chelating activity. Moreover, Ro did not exhibit cytotoxicity or dissipate the mitochondrial membrane potential (∆Ψ) in rat liver fibroblasts (BRL3A cells). To evaluate whether such antioxidant protective activity observed in vitro could also be achieved in vivo, a well-established model of hepatotoxicity induced by acute exposure to acetaminophen (AAP) was used. This model depletes GSH and promotes oxidative-stress-mediated tissue damage. The treatment of rats with 0.05% Ro , administered intraperitoneally for four days, resulted in inhibition of AAP-induced lipid peroxidation of the liver and the prevention of hepatotoxicity, maintaining alanine and aspartate aminotransferase (ALT/AST) levels equal to those of the normal, non-treated rats. Together, these findings highlight the potent antioxidant activity of rosemary, which is able to protect mitochondria from oxidative damage in vitro, and effects such as the antioxidant and hepatoprotective effects observed in vivo.

Pregestational hyperglycemia cause adverse effects on mothers and their offspring. We aimed to evaluate the maternal hyperglycemia influence on pre-embryos from diabetic rats and on their generations (daughters and granddaughters). Diabetes was induced in Sprague-Dawley rats. The mothers and their female pups were submitted to oral glucose tolerance test in adulthood. In day 4 of pregnancy, pre-embryos were collected for morphological analysis. The diabetic mother, daughter and granddaughter rats showed glucose intolerance and their pre-embryos presented developmental delay, degeneration and losses compared to the nondiabetic group. Thus, maternal diabetes transgenerationally affects embryos at early development, which contributes for embryofetal losses.

Aims: To evaluate the morphological changes in the pancreatic islet cells of adult female pups born to diabetic rats and fed a high-fat diet., Main Methods: Female Sprague-Dawley rats were distributed into four experimental groups (n = 10 animals/group): 1) female pups from non-diabetic dams and fed a standard diet (OC/SD), 2) female pups from non-diabetic dams and fed a high-fat (OC/HFD), 3) female pups from diabetic dams and fed a standard diet (OD/SD) and 4) female pups from diabetic dams and fed a high-fat diet (OD/HFD). In adulthood, the rats were submitted to the oral glucose tolerance test and later euthanized to collect the pancreas for the analysis of pancreatic islets., Key Findings: The OC/HFD and OD/SD groups showed an increased percentage of cells immunostained for insulin and a decreased percentage and intensity of staining for somatostatin. The OD/HFD group showed an increased percentage of cells immunostained for insulin and glucagon and a higher staining intensity for glucagon. There was a progressive increase in blood glucose in the OC/HFD, OD/SD, and OD/HFD groups., Significance: The association between maternal diabetes and/or the administration of high-fat diet-induced changes in the pancreatic hormonal triad of female pups in adulthood. In turn, these changes in the pancreatic islets are not capable of causing decreased blood glucose in the offspring, contributing to the development of glucose intolerance in adulthood., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: We conducted a meta-analysis to investigate whether diabetes induced by a high-fat diet (HFD) has the potential to alter the process of autophagy in the murine liver., Methods: A systematic literature search was performed with electronic databases (PubMed, EMBASE, Web of Science). Study design, population, intervention, outcome, and risk of bias were analyzed. Given the availability of studies, a quantitative meta-analysis including 23 studies was performed., Key Findings: The search found 5754 articles, with 48 matching the eligibility criteria, comprising of 1033 animals. The meta-analysis showed that diabetic murines fed with HFD presented an absence of p62 degradation (SMD 4.63, 95 % CI 2.02 to 7.24, p = 0.0005; I 2  = 77 %), higher expression of p-mTOR/mTOR (SMD 5.20, 95 % CI 1.00 to 9.39, p = 0.01; I 2  = 78 %), and a decreased p-AMPK/AMPK ratio (SMD -2.02, 95 % CI -3.96 to -0.09, p = 0.04; I 2  = 85 %) when compared to nondiabetic murines. When associated with streptozotocin, the animals presented decreased ATG-7 and LC3-II. The meta-regression results showed a decrease in autophagy responses due to increased glycemic levels, fat content, and long-term exposure to HFD, and advanced animal age. The common and species-specific protein responses were also consistent with the inhibition of autophagy., Significance: The normal process of autophagy mechanisms in the liver is less competent after HFD consumption. The destabilization of (auto)phagolysosomes contributes to the perpetuation of diabetes, metabolic dysfunction-associated fatty liver disease, and cell death., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Clinical and epidemiological studies show that maternal hyperglycemia can change the programming of offspring leading to transgenerational effects. These changes may be related to environmental factors, such as high-fat diet (HFD) consumption, and contribute to the comorbidity onset at the adulthood of the offspring. The objective of this study was to evaluate the hyperglycemic intrauterine environment, associated or not with an HFD administered from weaning to adult life on the periovarian adipose tissue of rat offspring Maternal diabetes was chemically induced by Streptozotocin. Female offsprings were randomly distributed into four experimental groups (n = 5 animals/group): Female offspring from control or diabetic mothers and fed an HFD or standard diet. HFD was prepared with lard enrichment and given from weaning to adulthood. On day 120 of life, the rats were anesthetized and sacrificed to obtain adipose tissue samples. Then, the hyperglycemic intrauterine environment and HFD fed after weaning caused a higher body weight, total fat, and periovarian fat in adult offspring, which could compromise the future reproductive function of these females. These rats showed higher adiposity index and adipocyte area, contributing to hypertrophied adipose tissue. Therefore, maternal diabetes itself causes intergenerational changes and, in association with the HFD consumption after weaning, exacerbated the changes in the adipose tissue of adult female offspring.

Maternal diabetes-mediated fetal programming is widely discussed, however, it is important to define the extent to which intrauterine hyperglycemia interferes with the health of female pups, along with determining whether these changes can be perpetuated across generations. This study aimed to evaluate the effects of maternal diabetes on fetal programming and the repercussions on the metabolism of pregnant and nonpregnant female pups. Diabetes status was induced (diabetic group-D) using streptozotocin (a beta cell cytotoxic drug) on the fifth postnatal day of female rats, while controls received a citrate buffer (Control-C). In adulthood, the rats were mated to obtain their female pups. At 90 days of age, half of the female pups were mated (preg) and the other half continued virgin (Npreg). Furthermore, they were distributed into four groups: OC/Npreg and OC/preg-female pups from control mothers; OD/Npreg and OD/preg-female pups from diabetic mothers. At 115 days of life and/or 17 days of pregnancy, the oral glucose tolerance test (OGTT) was performed with blood collection for insulin measurement. At 120 days of life and/or 21 days of pregnancy, the rats were anesthetized and euthanized to determine their blood oxidative stress status. The OD/Npreg group showed glucose intolerance during OGTT ( p  < 0.0001), while the OD/preg group showed increased insulin secretion during OGTT ( p  < 0.0001) and insulin resistance (IR; p  = 0.0027). An increase in homeostatic model assessment β was shown in the pregnant groups, regardless of maternal diabetes ( p  < 0.0001). The OD/preg group presented increased thiobarbituric acid reactive substances ( p  < 0.0001) and -SH levels ( p  = 0.0005) and decreased superoxide dismutase activity ( p  = 0.0063). Additionally, small fetuses for gestational age ( p  < 0.0001) were found in these rats. In conclusion, exposure to maternal hyperglycemia compromises the glycemic metabolism of female pups before and during pregnancy and causes oxidative stress, IR, and impaired fetal growth during pregnancy.

The aim of this systematic review and meta-analysis was to analyze the influence of a maternal and/or offspring high-fat diet (HFD) on the morphology of the offspring adipocytes and amount of food and energy consumption. The search was conducted through Pubmed, EMBASE, and Web of Science databases up to October 31st, 2021. The outcomes were extracted and pooled as a standardized mean difference with random effect models. 5,004 articles were found in the databases. Of these, only 31 were selected for this systematic review and 21 were included in the meta-analysis. A large discrepancy in the percentage of fat composing the HFD (from 14% to 62% fat content) was observed. Considering the increase of adipose tissue by hyperplasia (cell number increase) and hypertrophy (cell size increase) in HFD models, the meta-analysis showed that excessive consumption of a maternal HFD influences the development of visceral white adipose tissue in offspring, related to adipocyte hypertrophy, regardless of their HFD or control diet consumption. Upon following a long-term HFD, hyperplasia was confirmed in the offspring. When analyzing the secondary outcome in terms of the amount of food and energy consumed, there was an increase of caloric intake in the offspring fed with HFD whose mothers consumed HFD. Furthermore, the adipocyte hypertrophy in different regions of the adipose tissue is related to the sex of the pups. Thus, the adipose tissue obesity phenotypes in offspring are programmed by maternal consumption of a high-fat diet, independent of postnatal diet., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

The experiment was conducted at Araí & Zumbi farm on sixty healthy Dorper ewes to compare blood glucose, hormonal profile, and insulin resistance evaluation in sheep from conception until 48 h postpartum in single and twin pregnancies. All experimental ewes raised under semi-intensive management system. Sixty animals were selected from 150 estrous synchronized and pregnant ewes. The animals were divided into two groups based on single (G1, n = 30) and twin pregnancies (G2, n = 30). Blood samples were collected at nine time points: immediately after fixed-time artificial insemination (D0); at 30 days (D30), 90 days (D90), 120 days (D120), 130 days (D130), and 140 days (D140) of pregnancy; on the delivery day (DD); and at 24 h (PD1) and 48 h (PD2) postpartum. The results of blood glucose, insulin, glucagon, cortisol, and thyroid hormones (T3 and T4) levels showed significant differences over the analyzed sample times; however, only cortisol showed differences within groups, with the G1 having higher values than the G2 group. The interaction of the groups × nine sample times showed a significant result (P = 0.001) only for glucagon. The number of fetuses directly interfered with the glucagon profile throughout gestation. The glucose, cortisol, glucagon, and the homeostatic model assessment for insulin resistance (HOMA IR) concentrations increased at DD and decreased at PD1 and PD2. T3 and T4 showed different behaviors among the sample times. T3 values presented a decrease from D0 to D90, followed by an increase from D90 to DD. Otherwise, for T4 values, a decrease from D90 to D130 was observed, followed by an increase from D130 to D140. Despite the changes found in the endocrine system and metabolism in Dorper ewes throughout pregnancy, the nutritional management ensured a healthy status during pregnancy, delivery, and postpartum in single and twin gestation, whose HOMA IR profiles remained identical., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Ethnopharmacological Relevance: Curatella americana L. is employed in popular medicine for treating diabetes. However, the understanding around its outcomes during pregnancy is unclear., Aim of the Study: To evaluate the phytochemical and hypoglycemic analysis of the C. americana extract and its maternal-fetal effect on diabetic rats., Materials and Method: Diabetes was chemically induced 24 h after birth in Wistar female newborn rats. At adulthood, after diabetes status confirmation, the rats were mated and randomized into four experimental groups: Nondiabetic (Control): given water; Treated: given C. americana extract; Diabetic, and Treated Diabetic rats. The aqueous extract of C. americana leaves (300 mg/kg) was administered daily through oral route during pregnancy. Maternal toxicity and biochemical profile, reproductive outcomes, fetal development, and phenolic composition and biogenic amines in aqueous extract were analyzed., Results and Conclusion: Phytochemical analysis revealed that the main phenolic components are 3-hydroxytyrosol, kaempferol, and quercetin, while tryptophan and putrescine derivatives were identified as the dominant amines. C. americana extract treatment improved the lipid profile, although no effect on hyperglycemic control in diabetic rats was observed. Maternal diabetes or C. americana extract caused embryo losses confirmed by the lower number of pre-embryos in early pregnancy and higher percentage of abnormal morphologically pre-embryos. C. americana extract previously caused premature pre-embryo fixation before implantation window in nondiabetic and diabetic mothers and intrauterine growth restriction in the fetuses of treated nondiabetic dams, complicating the embryo fetal development. These findings reinforce the caution of indiscriminate use of medicinal plants, especially during pregnancy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Maternal diabetes-induced fetal programming predisposes offspring to type 2 diabetes, cardiovascular disease, and obesity in adulthood. However, lifelong health and disease trajectories depend on several factors and nutrition is one of the main ones. We intend to understand the role of maternal diabetes-induced fetal programming and its association with a high-fat diet during lifelong in the female F1 generation focusing on reproductive outcomes and the possible changes in physiological systems during pregnancy as well as the repercussions on the F2 generation at birth. For this, we composed four groups: F1 female pups from control (OC) or from diabetic dams (OD) and fed with standard (SD) or high-fat diet from weaning to full-term pregnancy. During pregnancy, glucose intolerance and insulin sensitivity were evaluated. In a full-term pregnancy, the maternal blood and liver were collected to evaluate redox status markers. The maternal blood, placental tissue, and fetal blood (pool) were collected to evaluate adiponectin and leptin levels. Maternal reproductive parameters were evaluated as well. Maternal diabetes and high-fat diet consumption, in isolation, were both responsible for increased infertility rates and fasting glucose levels in the F1 generation and fetal growth restriction in the F2 generation. The association of both conditions showed, in addition to those, increased lipoperoxidation in maternal erythrocytes, regardless of the increased endogenous antioxidant enzyme activities, glucose intolerance, decreased number of implantation sites and live fetuses, decreased litter, fetal and placental weight, increased preimplantation losses, and increased fetal leptin serum levels. Thus, our findings show that fetal programming caused by maternal diabetes or lifelong high-fat diet consumption leads to similar repercussions in pregnant rats. In addition, the association of both conditions was responsible for glucose intolerance and oxidative stress in the first generation and increased fetal leptin levels in the second generation. Thus, our findings show both the F1 and F2 generations harmed health after maternal hyperglycemic intrauterine environment and exposure to a high-fat diet from weaning until the end of pregnancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sinzato, Paula, Gallego, Moraes-Souza, Corrente, Volpato and Damasceno.)

Context: Excessive consumption of high-fat diets has increased in the population over time and is harmful to female fertility., Objective: To investigate and discuss the effects of a high-fat diet on ovarian follicles in rodents., Data Source: A systematic literature search of PubMed, EMBASE, Web of Science, and SCOPUS was carried out., Data Extraction: Study characteristics, including study design, population, intervention, outcome, and risk of bias were analyzed., Data Analysis: Twenty-two articles were included in a systematic review. Given the availability of studies, a quantitative meta-analysis included 12 studies that were performed for outcomes. There was a decrease in primordial follicles in female rodents that received a high-fat diet compared with the standard diet group. The offspring of mothers exposed to a high-fat diet showed an increased number of cystic follicles and a decreased number of secondary follicles and antral follicles, compared with the control diet group. Therefore, these high-fat diet-induced follicular alterations might impair the fertility of dams and their female newborns., Conclusion: The consumption of a high-fat diet causes damage to ovarian follicular development, and this commitment will persist in the next generation., Systematic Review Registration: PROSPERO registration no. CRD42019133865., (© The Author(s) 2021. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We evaluated the influence of the hyperglycemic intrauterine environment and postweaning consumption of a high-fat diet (HFD) on the glycemia, insulin, lipid, and immunological profile of rat offspring in adulthood. Female rats received citrate buffer (Control-C) or Streptozotocin (a beta cell-cytotoxic drug to induce diabetes-D) on postnatal day 5. In adulthood, these rats were mated to obtain female offspring, who were fed a standard diet (SD) or HFD from weaning to adulthood (n = 10 rats/group). OC/SD and OC/HFD represent female offspring of control mothers and received SD or HFD, respectively; OD/SD and OD/HFD represent female offspring of diabetic mothers and received SD or HFD, respectively. At adulthood, the oral glucose tolerance test (OGTT) was performed and, next, the rats were anesthetized and euthanized. Pancreas was collected and analyzed, and adipose tissue was weighted. Blood samples were collected to determine biochemical and immunological profiles. The food intake was lower in HFD-fed rats and visceral fat weight was increased in the OD/HFD group. OC/HFD, OD/SD, and OD/HFD groups presented glucose intolerance and lower insulin secretion during OGTT. An impaired pancreatic beta-cell function was shown in the adult offspring of diabetic rats, regardless of diet. Interleukin (IL)-6 and IL-10 concentrations were lower in the OD/HFD group and associated to a low-grade inflammatory condition. The fetal programming was responsible for impaired beta cell function in experimental animals. The association of maternal diabetes and postweaning HFD are responsible for greater glucose intolerance, impaired insulin secretion and immunological change., (© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The hypertension incidence and its complication on pregnant women are growing and can lead to adverse consequences on their fetuses. However, it is known that regular exercise practice can be healthful to hypertensive pregnant women but harmful to fetal growth. So, the objective of this study was to evaluate the effects of exercise beginning before pregnancy or during pregnancy on the maternal blood pressure and reproductive outcome and on the fetal development of spontaneously hypertensive rats (SHR). Pregnant SHR were randomly distributed into three experimental groups: (1) SHR-Control, non-exercised; (2) SHR-Ex0, rats submitted to physical exercise (swimming program) from day zero to 20 of pregnancy; (3) and SHR-ExPr, rats submitted to swimming program before and during pregnancy. At end of pregnancy (day 21), the rats were anesthetized, and reproductive parameters and fetal development were assessed. Blood pressure was reduced at the end of pregnancy in all the groups. Regardless of swimming exposure time, there was reduced maternal weight gain. The exercise decreased fetal weight at term pregnancy, with a higher percentage of small for gestational age (SGA) fetuses and lower number ossification sites, indicating intrauterine growth restriction (IUGR). In conclusion, our findings provide insight to support that swimming exercise in pregnant SHR impairs fetal development, causing IUGR and visceral malformations. Therefore, the indication of physical exercise must be defined very carefully, as it can compromise fetal development., (© 2021. Society for Reproductive Investigation.)

Maternal exposure to the high-fat diet (HFD) during gestation or lactation can be harmful to both a mother and offspring. The aim of this systematic review was to identify and evaluate the studies with animal models (rodents) that were exposed to the high-fat diet during pregnancy and/or lactation period to investigate oxidative stress and lipid and liver enzyme profile of mothers and their offspring. The electronic search was performed in the PUBMED (Public/Publisher MEDLINE), EMBASE (Ovid), and Web of Science databases. Data from 77 studies were included for qualitative analysis, and of these, 13 studies were included for meta-analysis by using a random effects model. The pooled analysis revealed higher malondialdehyde levels in offspring of high-fat diet groups. Furthermore, the pooled analysis showed increased reactive oxygen species and lower superoxide dismutase and catalase in offspring of mothers exposed to high-fat diet during pregnancy and/or lactation. Despite significant heterogeneity, the systematic review shows oxidative stress in offspring induced by maternal HFD., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021 R. Q. Moraes-Souza et al.)

Embryo-fetal exposure to maternal disorders during intrauterine life programs long-term consequences for the health and illness of offspring. In this study, we evaluated whether mild diabetic rats that were given high-fat/high-sugar (HF/HS) diet presented maternal and fetal changes at term pregnancy. Female rats received citrate buffer (non-diabetic-ND) or streptozotocin (diabetic-D) after birth. According to the oral glucose tolerance test (OGTT), the experimental groups ( n = 11 animals/group) were composed of non-diabetic and diabetic receiving standard diet (S) or HF/HS diet. High-fat/high-sugar diet (30% kcal of lard) in chow and water containing 5% sucrose and given 1 month before mating and during pregnancy. During and at the end of pregnancy, obesity and diabetes features were determined. After laparotomy, blood samples, periovarian fat, and uterine content were collected. The diabetic rats presented a higher glycemia and percentage of embryonic losses when compared with the NDS group. Rats DHF/HS presented increased obesogenic index, caloric intake, and periovarian fat weight and reduced gravid uterus weight in relation to the other groups. Besides, this association might lead to the inflammatory process, confirmed by leukocytosis. Obese rats (NDHF/HS and DHF/HS) showed higher triglyceride levels and their offspring with lower fetal weight and ossification sites, indicating intrauterine growth restriction. This finding may contribute to vascular alterations related to long-term hypertensive disorders in adult offspring. The fetuses from diabetic dams showed higher percentages of skeletal abnormalities, and DHF/HS dams still had a higher rate of anomalous fetuses. Thus, maternal diabetes and/or obesity induces maternal metabolic disorders that contribute to affect fetal development and growth., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Araujo-Silva, Santos-Silva, Lourenço, Barros-Barbosa, Moraes-Souza, Soares, Karki, Paula, Sinzato, Damasceno and Volpato.)

The present study aims to confirm if the moderate-intensity swimming has successful glycemic control and non-toxic oxidative stress levels and to verify the influence on pancreatic adaptations, embryo implantation, and placental efficiency. Female Wistar rats were randomly distributed to obtain mildly diabetic by streptozotocin induction at birth and the non-diabetic females given vehicle. At adulthood, pregnant rats were put at random into sedentary non-diabetic rats (ND); exercise non-diabetic rats (NDEx); sedentary diabetic rats (D); and exercise diabetic rats (DEx). The rats of the groups submitted to moderate intensity carried loads equivalent to 4% of body weight. On day 17 of gestational day, all rats were submitted to oral glucose tolerance test (OGTT). Next day (GD18), the rats were anesthetized and killed to count implantation sites and to collect placentas, blood, and muscle samples for biochemical biomarkers and pancreas for immunohistochemical analysis. The moderate exercise used was not sufficient to stimulate the aerobic pathway but presented positive results on glucose metabolism, lower embryo postimplantation loss, and pancreatic morphology compared with the sedentary diabetic group. However, the DEx group showed muscular damage, decreased antioxidant defense, and lipid peroxidation. Thus, the moderate-intensity exercise reduces glycemic levels during OGTT and causes no damage to non-diabetic rats related to other analyzed parameters in this study. The exercised diabetic rats present better glycemic metabolism in OGTT, islet pancreatic morphology, and embryofetal development. However, it is necessary an adjustment in this exercise intensity to improve the effectiveness of aerobic training for reduction of maternal muscular and lipid membrane damages., (© 2021. Society for Reproductive Investigation.)

Animal models are widely used for studying diabetes in translational research. However, methods for induction of diabetes are conflicting with regards to their efficacy, reproducibility and cost. A comparison of outcomes between the diabetic models is still unknown, especially full-term pregnancy.To understand the comparison, we analyzed the streptozotocin (STZ)-induced diabetes at three life-different moments during the neonatal period in Sprague-Dawley female rats: at the first (D1), second (D2) and fifth (D5) day of postnatal life. At adulthood (90 days; D90), the animals were submitted to an oral glucose tolerance test (OGTT) for diabetic status confirmation. The diabetic and control rats were mated and sacrificed at full-term pregnancy for different analyses. Group D1 presented a higher mortality percentage after STZ administration than groups D2 and D5. All diabetic groups presented higher blood glucose levels as compared to those of the control group, while group D5 had higher levels of glycemia compared with other groups during OGTT. The diabetic groups showed impaired reproductive outcomes compared with the control group. Group D1 had lower percentages of mated rats and D5 showed a lower percentage of a full-term pregnancy. Besides that, these two groups also showed the highest percentages of inadequate fetal weight. In summary, although all groups fulfill the diagnosis criteria for diabetes in adult life, in our investigation diabetes induced on D5 presents lower costs and higher efficacy and reproducibility for studies involving diabetes-complicated pregnancy.

Background: Exercise is commonly recommended to control hyperglycemia, including during pregnancy. We conducted this study to understand the potential benefits and risks of exercise during pregnancy of women with diabetes. Specifically, we evaluated the effects of swimming on a diabetic rat during pregnancy and assayed maternal-fetal parameters., Methods: Diabetes was induced in the female newborn from Wistar rats by the streptozotocin administration on first postnatal day. At 110 days of life, after confirm mild symptoms of diabetes, the rats were mated and randomly distributed into four experimental groups (minimum of 13 animals/group): Control (C)-nondiabetic animals without swimming; Control and Exercise (CEx)-nondiabetic animals submitted to swimming; Mild Diabetic (MD)-diabetic animals without swimming; Mild Diabetic and Exercise (MDEx)-diabetic animals submitted to swimming. The swimming program was performed from day 7 to 21 of pregnancy. Maternal parameters were evaluated during the pregnancy period. On day 21 of pregnancy, the rats were sacrificed and maternal and fetal parameters analyzed., Results: There are no alterations in body weight, food consumption, water intake, and reproductive outcomes among the groups. The swimming program did not normalize maternal glycemia and other biochemical biomarkers. The diabetes and exercise combination increased organ weight. The fetuses born to these exercising diabetic rats had reduced fetal weight and increased skeletal anomalies (mainly incomplete ossification of sternebra)., Conclusion: The intense swimming exercise imposed on female rats during pregnancy impaired maternal metabolic repercussions, contributing to intrauterine growth restriction and fetal skeletal anomalies., (© 2020 Wiley Periodicals LLC.)

This study aimed at evaluating the levels of different maternal exercise intensities on maternal and fetal outcomes. Wistar rats were mated and the pregnant rats were distributed into four experimental groups (n = 13 animals/group): Control (Not exercise group - 0% of the anaerobic threshold- AT), mild (20%), moderate (80%), and heavy-exercise intensity (140% of AT). These AT were matched to the load of 0, 1, 4 and 7% of the body weight of the animal related to swimming-induced physical intensity. In pregnancy, biomarkers related to maternal blood gases, oxidative stress, metabolism, and reproductive performance, and outcomes of their offspring were analyzed. The mild and moderate-swimming caused no change on implantation, live fetus numbers and oxidative stress status. However, the rats submitted to mild-exercise presented respiratory alkalosis and the heavy-exercise group showed respiratory acidosis. In addition, fetuses of the heavy-exercise dams were smaller for gestational age and lower serum adiponectin levels compared to those of other groups. In conclusion, the moderate-exercise intensity caused beneficial effects for maternal environment and the mild and moderate-exercise presented similar fetal repercussions. Nevertheless, the heavy-exercise intensity caused maternal metabolic alterations that damaged the fetal growth. Therefore, these findings confirm that physical intensity should be carefully conducted to avoid maternal complications and, consequently, compromised fetal repercussions.

The objective of the present study was to evaluate maternal reproductive performance, body weight, and frequency of external and internal anomalies of newborns of Wistar Audiogenic Rat (WAR) females as compared with Wistar rats. The adult WAR and Wistar rats were mated within their respective strains. After confirming the pregnancy, the body weights were weekly evaluated. On day 21 of pregnancy, the female rats were anesthetized and sacrificed to evaluate the maternal reproductive outcomes and biochemical profile, newborn weight, and external and internal anomalies. The WAR strain gained less weight during the pregnancy and presented hyperproteinemia, hypertriglyceridemia, and embryonic losses concerning Wistar rats, suggesting an inadequate intrauterine condition for embryonic development and fetal viability. WAR also presented a higher percentage of newborns classified as small for gestational age related to intrauterine growth restriction, which was confirmed by the lower number of ossification centers. There was a higher percentage of skeletal anomalies compared with fetuses of the Wistar dams, confirming their greater susceptibility during the formation and development of their skeletal system. Thus, the WAR presents physiological alterations compromising the viability of their embryos and fetuses, leading to impaired development of the newborns.

Preexisting/pregestational diabetes enhances the risk of birth defects. Several factors have been involved during the implantation process, such as cytokines (granulocyte-macrophage-colony-stimulating factor [GM-CSF]). The objective was to evaluate the effects of two levels of diabetes on the redox status of preimplantation embryos during the implantation process to comprehend how both are involved in embryo and fetal viability against maternal diabetes. Female Sprague-Dawley rats received streptozotocin at birth (mild diabetes [MD]) or at adulthood (severe diabetes [SD]) to obtain two experimental diabetes intensities. After confirming the diabetic status, the nondiabetic and diabetic groups were mated around day 110 of life. At gestational day (GD) 21, fetuses were assessed for viability and malformations and ovaries for embryo loss before implantation. Other pregnant nondiabetic and diabetic rats were sacrificed at GD2-4 for maternal and preimplantation embryo oxidative stress markers, maternal serum insulin, uterine fluid GM-CSF, and preimplantation embryo morphological analysis. MD and SD caused abnormal redox levels, lower GM-CSF and insulin levels during the preimplantation period, and embryonic loss before implantation. SD caused lower fetal viability and higher fetal malformation percentages at GD21. The SD dam-derived preimplantation embryos presented lower glutathione levels and higher thiobarbituric acid reactive substances concentration at GD3 and an increased frequency of abnormal preimplantation embryos at GD4. In conclusion, preexisting diabetes leads to complications in the implantation process. Furthermore, maternal oxidative stress and other metabolic changes alter the redox state and morphological structure of preimplantation embryos, contributing to damaged growth and development in late pregnancy., (© The Author(s) 2020. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To determine the occurrence and severity of pregnancy-specific urinary incontinence (PSUI) in women with gestational hyperglycaemia, and its impact on quality of life (QoL) over the first year post partum., Study Design: Three hundred and eighty-eight pregnant women with PSUI were distributed into two groups (normoglycaemic and hyperglycaemic) and analysed at five timepoints during pregnancy and the first year post partum. Gestational hyperglycaemia was defined according to the criteria of the American Diabetes Association and the glucose profile test. Relationships with outcome were analysed using Chi-squared test for categorical variables and Student's t-test for quantitative variables., Results: The overall prevalence rate of PSUI was 54.1 %, with prevalence rates of 43.3 % and 56.7 % in normoglycaemic and hyperglycaemic Brazilian pregnant women, respectively. Women with gestational hyperglycaemia had a higher amount of urine loss (p < 0.0027), frequency of UI (p < 0.0014), impact of UI on QoL (p < 0.0001), severity of UI (p = 0.0003) and total scores on the International Consultation on Incontinence Questionnaire-Urinary Incontinence-Short Form (ICIQ-SF) and Incontinence Severity Index (ISI) (p<0.0001) at the two timepoints during pregnancy; and a higher amount of urine loss (p = 0.0079), frequency of UI (p = 0.0382), impact of UI on QoL (p < 0.0001), severity of UI (p = 0.0053) and questionnaire scores (p < 0.0001 for ICIQ-SF and p = 0.003 for ISI) over the first year post partum., Conclusions: PSUI in women with gestational hyperglycaemia worsens the occurrence and severity of UI, and the impact of UI on QoL over the first year post partum. These results emphasize the interaction between PSUI, gestational hyperglycaemia and long-term maternal outcome., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Oxidative stress occurs when there is greater than optimal production of reactive oxygen species (ROS) or an antioxidant system failure. Calves produced using in vitro fertilization (IVF) or cloning (CA) have greater mortality rates, with greater incidence of respiratory diseases, which could be explained by the deleterious outcomes from oxidative stress. Calves were studied that were produced using: artificial insemination (AI; n = 20), in vitro fertilization (IVF; n = 15) or cloning (CA; n = 15). Blood samples were collected at 6, 12, 24 and 48 h subsequent to the time of birth. The cloned calves had greater ROS production from lipid peroxidation, with greater thiobarbituric acid reactive substances. This factor was associated with a lesser amount of superoxide dismutase in the CA. Calves produced using IVF had a greater activity of catalase and glutathione peroxidase, either due to greater production of hydrogen peroxide or greater efficiency of enzymatic response of these neonates. Calves produced using AI had greater concentrations ​​of reduced thiol groups. These associated factors may indicate there is greater oxidative stress in calves produced by IVF and cloning than with use of AI, however in these calves there was an effective response to these oxidative stressors within 48 h subsequent to birth. Hence, calves produced using IVF and by cloning have greater ROS production when compared to calves produced using AI. The calves produced using IVF, however, had a greater enzymatic activity or were more efficient in adapting to ROS when compared to calves produced by cloning., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Phyllanthus niruri is a well-known plant for its therapeutic purposes to treat various diseases, being widely used by the population, mainly by women. However, there is no scientific confirmation of the effects of use during pregnancy., Aim of the Study: Evaluating the effect of Phyllanthus niruri aqueous extract on the maternal toxicity, reproductive outcomes and fetal anomaly incidence in rats., Materials and Methods: Pregnant rats were distributed into four experimental groups: Control = treated with water (vehicle); Treated 150 = treated with P. niruri at dose 150 mg/kg and; Treated 300 = treated with P. niruri at dose 300 mg/kg; and Treated 600 = treated with P. niruri at dose 600 mg/kg. The rats were treated by intragastric route (gavage) with P. niruri or vehicle (water) from gestational day 0 to 21. At day 21 of pregnancy, maternal reproductive outcomes, biochemical profile and maternal renal tissue were evaluated. The fetuses and placentas were collected and analyzed., Results: Treatment with P. niruri did not alter the reproductive performance outcomes of rats. However, treated 600 group presented with changes in maternal kidney weight and morphology. The plant did not present teratogenic effect, but caused fetal macrosomia and increased ossification sites., Conclusion: Treatment with aqueous extract of P. niruri administered during gestation did not cause reproductive toxicity, but led to changes in maternal kidneys and in offspring weight, showing that the leaf extract of this plant can produce detrimental effects during pregnancy., Competing Interests: Declaration of competing interest There are no conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Hancornia speciosa is usually used in Brazilian folk medicine to treat diabetes. The hypothesis of the present study is that this medicinal plant exerts beneficial effects on hyperglycemia, preventing diabetic complications. Therefore, the aim of this study was to evaluate the treatment effect of the aqueous extract of H. speciosa leaves on metabolic parameters of diabetic rats., Methods: The H. speciosa extract (400 mg/Kg) was administered to both nondiabetic and severely diabetic female Wistar rats by gavage. The Oral Glucose Tolerance Test was performed and the area under the curve (AUC) was estimated on day 17 of pregnancy. After 21 days of treatment, the animals were anesthetized and killed to obtain organ weights. Blood samples were collected for an analysis of serum biochemical parameters., Results: After treatment with the H. speciosa extract, the parameters of nondiabetic rats remained unchanged. In treated diabetic rats, glycemia, AUC, dyslipidemia parameters, and relative organ weights were decreased compared with nontreated diabetic rats. Severely diabetic rats showed decompensated hyperglycemia, polydipsia, hyperphagia and dyslipidemia. However, the aqueous extract of H. speciosa leaves decreased diabetes complications (indicating a lack of toxicity), reduced blood glucose levels, and exerced lipid-lowering effects., Conclusion: Based on or findings, the H. speciosa leaf extract may be a safe and promising candidate treatment for diabetes and other diseases.

Background and Objective: In the present study, we compared the effect of diabetic pregnancy on the rectus abdominis muscle (RAM) in humans and rats. We hypothesized that our animal model could provide valuable information about alterations in the RAM of women with Gestational Diabetes (GDM)., Method: Newborns female rats (n = 10/group) were administered streptozotocin (100 mg/kg body weight) subcutaneously and were mated on reaching adulthood, to develop the mild hyperglycemic pregnant (MHP) rat model. At the end of pregnancy, the mothers were sacrificed, and the RAM tissue was collected. Pregnant women without GDM (non-GDM group; n = 10) and those diagnosed with GDM (GDM group; n = 8) and undergoing treatment were recruited, and RAM samples were obtained at C-section. The RAM architecture and the distribution of the fast and slow fibers and collagen were studied by immunohistochemistry., Results: No statistically significant differences in the maternal and fetal characters were observed between the groups in both rats and women. However, significant changes in RAM architecture were observed. Diabetes in pregnancy increased the abundance of slow fibers and decreased fast fiber number and area in both rats and women. A decrease in collagen distribution was observed in GDM women; however, a similar change was not observed in the MHP rats., Conclusion: Our results indicated that pregnancy- associated diabetes- induced similar structural adaptations in the RAM of women and rats with slight alterations in fiber type number and area. These findings suggest that the MHP rat model can be used for studying the effects of pregnancy-associated diabetes on the fiber structure of RAM., Competing Interests: The authors have declared that no competing interests exist.