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Gestational exposure to titanium dioxide nanoparticles (TiO

BACKGROUND: Emerging research suggests health effects in offspring after parental chemical exposures before conception. Many future mothers are exposed to potent chemicals at work, but potential offspring health effects are hardly investigated.OBJECTIVE: We sought to investigate childhood asthma in relation to mother's occupational exposure to cleaning products and disinfectants before conception.METHODS: The multicenter Respiratory Health In Northern Europe/Respiratory Health In Northern Europe, Spain and Australia generation study investigated asthma and wheeze starting at age less than 10 years in 3318 mother-offspring pairs. From an asthma-specific Job-Exposure Matrix and mothers' occupational history, we defined maternal occupational exposure to indoor cleaning agents (cleaning products/detergents and disinfectants) starting before conception, in the 2-year period around conception and pregnancy, or after birth. Never-employed mothers were excluded. Exposed groups include cleaners, health care workers, cooks, and so forth. Associations were analyzed using mixed-effects logistic regression and ordinary logistic regression with clustered robust SEs and adjustment for maternal education.RESULTS: Maternal occupational exposure to indoor cleaning starting preconception and continuing (n = 610) was associated with offspring's childhood asthma: odds ratio 1.56 (95% CI, 1.05-2.31), childhood asthma with nasal allergies: 1.77 (1.13-2.77), and childhood wheeze and/or asthma: 1.71 (95% CI, 1.19-2.44). Exposure starting around conception and pregnancy (n = 77) was associated with increased childhood wheeze and/or asthma: 2.25 (95% CI, 1.03-4.91). Exposure starting after birth was not associated with asthma outcomes (1.13 [95% CI, 0.71-1.80], 1.15 [95% CI, 0.67-1.97], 1.08 [95% CI, 0.69-1.67]).CONCLUSIONS: Mother's occupational exposure to indoor cleaning agents starting before conception, or around conception and pregnancy, was associated with more childhood asthma and wheeze in offspring. Considering potential implications for vast numbers of women in childbearing age using cleaning agents, and their children, further research is imperative.

Introduction Despite a wealth of epidemiological evidence that cumulative parental lifetime stress experiences prior to conception are determinant of offspring developmental trajectories, there is a lack of insight on how these previous stress experiences are stored and communicated intergenerationally. Preconception experiences may impact offspring development through alterations in transcriptional regulation of the placenta, a major determinant of offspring growth and sex-specific developmental outcomes. We evaluated the lasting influence of maternal and paternal preconception stress (PCS) on the mid-gestation placenta and fetal brain, utilizing their transcriptomes as proximate readouts of intergenerational impact. Methods To assess the combined vs. dominant influence of maternal and paternal preconception environment on sex-specific fetal development, we compared transcriptional outcomes using a breeding scheme of one stressed parent, both stressed parents, or no stressed parents as controls. Results Interestingly, offspring sex affected the directionality of transcriptional changes in response to PCS, where male tissues showed a predominant downregulation, and female tissues showed an upregulation. There was also an intriguing effect of parental sex on placental programming where paternal PCS drove more effects in female placentas, while maternal PCS produced more transcriptional changes in male placentas. However, in the fetal brain, maternal PCS produced overall more changes in gene expression than paternal PCS, supporting the idea that the intrauterine environment may have a larger overall influence on the developing brain than it does on shaping the placenta. Discussion Preconception experiences drive changes in the placental and the fetal brain transcriptome at a critical developmental timepoint. While not determinant, these altered transcriptional states may underlie sex-biased risk or resilience to stressful experiences later in life.

IntroductionBacterial vaginosis (BV) and vaginal microbiota disruption during pregnancy are associated with increased risk of spontaneous preterm birth (SPTB), but clinical trials of BV treatment during pregnancy have shown little or no benefit. An alternative hypothesis is that vaginal bacteria present around conception may lead to SPTB by compromising the protective effects of cervical mucus, colonising the endometrial surface before fetal membrane development, and causing low-level inflammation in the decidua, placenta and fetal membranes. This protocol describes a prospective case-cohort study addressing this hypothesis.Methods and analysisHIV-seronegative Kenyan women with fertility intent are followed from preconception through pregnancy, delivery and early postpartum. Participants provide monthly vaginal specimens during the preconception period for vaginal microbiota assessment. Estimated date of delivery is determined by last menstrual period and first trimester obstetrical ultrasound. After delivery, a swab is collected from between the fetal membranes. Placenta and umbilical cord samples are collected for histopathology. Broad-range 16S rRNA gene PCR and deep sequencing of preconception vaginal specimens will assess species richness and diversity in women with SPTB versus term delivery. Concentrations of key bacterial species will be compared using quantitative PCR (qPCR). Taxon-directed qPCR will also be used to quantify bacteria from fetal membrane samples and evaluate the association between bacterial concentrations and histopathological evidence of inflammation in the fetal membranes, placenta and umbilical cord.Ethics and disseminationThis study was approved by ethics committees at Kenyatta National Hospital and the University of Washington. Results will be disseminated to clinicians at study sites and partner institutions, presented at conferences and published in peer-reviewed journals. The findings of this study could shift the paradigm for thinking about the mechanisms linking vaginal microbiota and prematurity by focusing attention on the preconception vaginal microbiota as a mediator of SPTB.

Resumen Los edulcorantes no calóricos (ENC) son aditivos de alimentos que se utilizan para sustituir azúcares y potencialmente para reducir la ingesta energética. Existe un debate científico en torno a los beneficios reales de su uso. Los ENC son sustancias ampliamente evaluadas en la literatura científica. Su seguridad es revisada por las agencias regulatorias internacionales del campo de la salud. Los profesionales de la salud y los consumidores con frecuencia carecen de educación e información rigurosa, objetiva y sustentada en la evidencia científica y el juicio clínico sobre el uso de aditivos en los alimentos. Los ENC se han empleado como sustitutos de la sacarosa, en especial por las personas con diabetes mellitus y obesidad. Sin embargo, se han planteado inquietudes relacionadas con su posible asociación con el parto pretérmino y con su uso durante el embarazo y la lactancia, ante la posibilidad de consecuencias metabólicas o de otra índole en la madre o en el neonato. Este análisis de la evidencia en ginecología y obstetricia presenta una revisión que intenta responder a preguntas que habitualmente se hacen al respecto los profesionales de la salud y sus pacientes. En este documento se evalúan diversas publicaciones científicas bajo el tamiz de la medicina basada en la evidencia y del marco regulatorio para aditivos de alimentos con el fin dilucidar si el uso de ENC en las mujeres durante las etapas críticas del embarazo y la lactancia supone o no un posible riesgo. Abstract Non-nutritive sweeteners (NNS) are food additives that have been used as a possible tool to reduce energy and sugar intake. There is a scientific debate around the real benefits of their use. NNS are substances widely evaluated in the scientific literature. Their safety is reviewed by international regulatory health agencies. Health professionals and consumers often lack education and objective information about food additives based on the best scientific evidence. NNS have been used as a substitute for sucrose, especially by people with diabetes mellitus and obesity. However, concerns related to their possible association with preterm birth have been raised, and also with their use during pregnancy and lactation because of the possibility of metabolic or other consequences in both the mother and offspring. This analysis of the evidence in gynecology and obstetrics presents a review of the most commonly asked questions regarding this matter by health professionals and their patients. This document evaluates a diversity of scientific publications under the sieve of evidence-based medicine and the regulatory framework for food additives to elucidate whether the use of NNS in women in these critical stages of pregnancy and breastfeeding represents a potential risk.

Current literature describes limited and controversial evidence on the associations between maternal preconception and first trimester exposure to particulate matter with a diameter ≤10 µm (PMWe conducted a case-control study involving 3086 OC cases and 7950 controls, registered in the Maternal and Child Health Certificate Registry in Liaoning Province between 2010 and 2015. PMMaternal PMOur study provides evidence that PM

We investigated if greenness and air pollution exposure in parents&rsquo, childhood affect offspring asthma and hay fever, and if effects were mediated through parental asthma, pregnancy greenness/pollution exposure, and offspring exposure. We analysed 1106 parents with 1949 offspring (mean age 35 and 6) from the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) generation study. Mean particulate matter (PM2.5 and PM10), nitrogen dioxide (NO2), black carbon (BC), ozone (O3) (&micro, g/m3) and greenness (normalized difference vegetation index (NDVI)) were calculated for parents 0&ndash, 18 years old and offspring 0&ndash, 10 years old, and were categorised in tertiles. We performed logistic regression and mediation analyses for two-pollutant models (clustered by family and centre, stratified by parental lines, and adjusted for grandparental asthma and education). Maternal medium PM2.5 and PM10 exposure was associated with higher offspring asthma risk (odds ratio (OR) 2.23, 95%CI 1.32&ndash, 3.78, OR 2.27, 95%CI 1.36&ndash, 3.80), and paternal high BC exposure with lower asthma risk (OR 0.31, 95%CI 0.11&ndash, 0.87). Hay fever risk increased for offspring of fathers with medium O3 exposure (OR 4.15, 95%CI 1.28&ndash, 13.50) and mothers with high PM10 exposure (OR 2.66, 95%CI 1.19&ndash, 5.91). The effect of maternal PM10 exposure on offspring asthma was direct, while for hay fever, it was mediated through exposures in pregnancy and offspring&rsquo, s own exposures. Paternal O3 exposure had a direct effect on offspring hay fever. To conclude, parental exposure to air pollution appears to influence the risk of asthma and allergies in future offspring.

Xenoestrogens are chemicals found in plant products, such as genistein (GEN), and in industrial chemicals, e.g., bisphenol A (BPA), present in plastics and other products that are prevalent in the environment. Early exposure to such endocrine disrupting chemicals (EDC) may affect brain development by directly disrupting neural programming and/or through the microbiome-gut-brain axis. To test this hypothesis, California mice (Peromyscus californicus) offspring were exposed through the maternal diet to GEN (250 mg/kg feed weight) or BPA (5 mg/kg feed weight, low dose- LD or 50 mg/kg, upper dose-UD), and dams were placed on these diets two weeks prior to breeding, throughout gestation, and lactation. Various behaviors, gut microbiota, and fecal metabolome were assessed at 90 days of age. The LD but not UD of BPA exposure resulted in individuals spending more time engaging in repetitive behaviors. GEN exposed individuals were more likely to exhibit such behaviors and showed socio-communicative disturbances. BPA and GEN exposed females had increased number of metabolites involved in carbohydrate metabolism and synthesis. Males exposed to BPA or GEN showed alterations in lysine degradation and phenylalanine and tyrosine metabolism. Current findings indicate cause for concern that developmental exposure to BPA or GEN might affect the microbiome-gut-brain axis.

Using a mouse model, our group recently described an association between chronic paternal alcohol use prior to conception and deficits in offspring growth. Here, we sought to determine the impact of alcohol exposure on male reproductive physiology and the association of sperm-inherited noncoding RNAs with the transmission of the observed growth defects. Alcohol exposure did not appreciably alter male reproductive physiology or fertility. However, chronic alcohol use reproducibly induced late-term fetal growth restriction in the offspring, which correlated with a shift in the proportional ratio of transfer RNA-derived small RNAs to Piwi-interacting RNAs, as well as altered enrichment of microRNAs miR21, miR30, and miR142 in alcohol-exposed sperm. Although our dataset share similarities to prior works examining the impact of paternal stress on offspring phenotype, we were unable to identify any changes in plasma corticosterone, indicating alcohol may alter sperm-inherited noncoding RNAs through distinct mechanisms.

While alcohol use disorder (AUD) is a highly heritable psychiatric disease, efforts to elucidate that heritability by examining genetic variation (e.g., single nucleotide polymorphisms) have been insufficient to fully account for familial AUD risk. Perhaps not coincidently, there has been a burgeoning interest in novel non-genomic mechanisms of inheritance (i.e., epigenetics) that are shaped in the male or female germ cells by significant lifetime experiences such as exposure to chronic stress, malnutrition, or drugs of abuse. While many epidemiological and preclinical studies have long pointed to a role for the parental preconception environment in offspring behavior, over the last decade many studies have implicated a causal relationship between the environmentally-sensitive sperm epigenome and intergenerational phenotypes. This critical review will detail the heritable effects of alcohol and the potential role for epigenetics.

The efforts of many neuroscientists are directed toward understanding the appreciable plasticity of the brain and behavior. In recent years, epigenetics has become a core of this focus as a prime mechanistic candidate for behavioral modifications. Animal models have been instrumental in advancing our understanding of environmentally driven changes to the epigenome in the developing and adult brain. This review focuses mainly on such discoveries driven by adverse environments along with their associated behavioral outcomes. While much of the evidence discussed focuses on epigenetics within the central nervous system, several peripheral studies in humans who have experienced significant adversity are also highlighted. As we continue to unravel the link between epigenetics and phenotype, discerning the complexity and specificity of epigenetic changes induced by environments is an important step toward understanding optimal development and how to prevent or ameliorate behavioral deficits bred by disruptive environments.

Background Particulate matter (particles < 2.5 μm [PM 2.5]) exposure during the in utero and postnatal developmental periods causes cardiac dysfunction during adulthood. Here, we investigated the potential priming effects of preconception exposure of PM 2.5 on cardiac function in adult offspring. Methods and Results Male and female friend leukemia virus b (FVB) mice were exposed to either filtered air (FA) or PM 2.5 at an average concentration of 38.58 μg/m3 for 6 hours/day, 5 days/week for 3 months. Mice were then crossbred into 2 groups: (1) FA male×FA female (both parents were exposed to FA preconception) and, (2) PM 2.5male×PM 2.5female (both parents were exposed to PM 2.5 preconception). Male offspring were divided: (1) preconception FA (offspring born to FA exposed parents) and, (2) preconception PM 2.5 (offspring born to PM 2.5 exposed parents) and analyzed at 3 months of age. Echocardiography identified increased left ventricular end systolic volume and reduced posterior wall thickness, reduced %fractional shortening and %ejection fraction in preconception PM 2.5 offspring. Cardiomyocytes isolated from preconception PM 2.5 offspring showed reduced %peak shortening, −dL/dT, TPS90 and slower calcium reuptake (tau). Gene and protein expression revealed modifications in markers of inflammation (IL‐6, IL‐15, TNFα, NFқB, CRP, CD26E, CD26P, intercellular adhesion molecule 1, and monocyte chemoattractant protein‐1) profibrosis (collagen type III alpha 1 chain), oxidative stress (NOS2), antioxidants (Nrf2, SOD, catalase), Ca2+ regulatory proteins (SERCA2a, p‐PLN, NCX), and epigenetic regulators (Dnmt1, Dnmt3a, Dnmt3b, Sirt1, and Sirt2) in preconception PM 2.5 offspring. Conclusions Preconception exposure to PM 2.5 results in global cardiac dysfunction in adult offspring, suggesting that abnormalities during development are not limited to the prenatal or postnatal periods but can also be determined before conception., See Editorial by Stapleton

Autoimmune skin diseases can occur in pregnancy, and the treatment is often required to control both maternal disease and fetal outcomes. Moreover, the control of mother's diseases and fetal health is a challenge for dermatologists because of the teratogenic effects of many drugs. So it is important to know exactly which drugs can be administrated in the different stages of pregnancy. Authors reviewing the literature and relying on daily dermatological experience agree that during pregnancy effective drug treatment of autoimmune diseases is possible with reasonable safety for the fetus/child and lactation. During pregnancy and lactation patients with autoimmune disorders should be evaluated carefully, and the benefit-risk of continued therapy should be reassessed. The points to consider presented in this review show that, despite limitations, effective drug treatment of autoimmune diseases is possible with reasonable safety for the fetus/child during pregnancy and lactation. Prior to conception it is necessary to explain to the patients what the risks of pregnancy are. It is preferred to avoid a pregnancy in active disease and replace treatment with an allowed therapy. During pregnancy it is necessary to avoid treatment with mycophenolate mofetil, cyclophosphamide and methotrexate. In some very particular cases, as life saver drug, cyclosporine and rituximab can be used. Finally, some drugs can be used monitoring the patient, in particular, systemic corticosteroid at low dosage, dapsone, azathioprine, iloprost and sildenafil.

Some human and animal studies have recently shown that maternal grandmother's smoking during pregnancy increases the risk of asthma in the grandchildren. We have investigated whether sex of the exposed parent and/or grandchild modifies the association between grandmaternal smoking and grandchild asthma.We formed a cohort study based on linkage of national registries with prospectively collected data over three generations. Smoking habits in early pregnancy were registered since 1982 and purchases of prescribed medication since 2005. In all, 10 329 children born since 2005 had information on maternal and grandmaternal smoking on both sides and were followed from birth up to 6 years of age. Ages when medication was purchased were used to classify the cohort into never, early transient (0-3 years), early persistent (0-3 and 4-6 years), and late-onset (4-6 years) phenotypes of childhood asthma.Maternal grandmother's smoking was associated with an increased odds of early persistent asthma after adjustment for maternal smoking and other confounders (odds ratio 1.29, 95% confidence interval 1.10-1.51). Grandchild sex did not modify the association. Paternal grandmother's smoking was not associated with any of the asthma phenotypes.Maternal but not paternal exposure to nicotine before conception was related to an increased risk of early persistent childhood asthma, but not other asthma phenotypes. Our findings are possibly consistent with a sex-specific mode of epigenetic transfer.

Overnutrition may lead to obesity. Maternal obesity may affect fertility not only via anovulation, but also through direct effects on oocytes and preimplantation embryos, indicating that the periconceptional period is sensitive to conditions of overnutrition. The periconceptional period includes from folliculogenesis to implantation. Animal model studies suggest that oocytes derived from obese females usually have a small size and mitochondrial abnormalities. These disruptions are probably induced by changes in the components of the ovarian follicular fluid. Experimental evidence also suggests that obesity may affect the microenvironment in oviducts and uterus, resulting in development of preimplantation embryos with reduced cell numbers and up-regulation of proinflammatory genes. However, further research is needed for in-depth characterization of the effects of maternal obesity during the periconceptional period.

Autism spectrum disorder (ASD), one of the most common childhood neurodevelopmental disorders (NDDs), is diagnosed in 1 of every 68 children. ASD is incredibly heterogeneous both clinically and aetiologically. The etiopathogenesis of ASD is known to be complex, including genetic, environmental and epigenetic factors. Normal epigenetic marks modifiable by both genetics and environmental exposures can result in epigenetic alterations that disrupt the regulation of gene expression, negatively impacting biological pathways important for brain development. In this chapter we aim to summarize some of the important literature that supports a role for epigenetics in the underlying molecular mechanism of ASD. We provide evidence from work in genetics, from environmental exposures and finally from more recent studies aimed at directly determining ASD-specific epigenetic patterns, focusing mainly on DNA methylation (DNAm). Finally, we briefly discuss some of the implications of current research on potential epigenetic targets for therapeutics and novel avenues for future work.

Drug addiction is a complex disorder which can be influenced by both genetic and environmental factors. Research has shown that epigenetic modifications can translate environmental signals into changes in gene expression, suggesting that epigenetic changes may underlie the causes and possibly treatment of substance use disorders. This chapter will focus on epigenetic modifications to DNA, which include DNA methylation and several recently defined additional DNA epigenetic changes. We will discuss the functions of DNA modifications and methods for detecting them, followed by a description of the research investigating the function and consequences of drug-induced changes in DNA methylation patterns. Understanding these epigenetic changes may provide us translational tools for the diagnosis and treatment of addiction in the future.

Congenital malformations might occur because of environmental or genetic factors, and sometimes occur because of unknown causes. Acetazolamide is a carbonic anhydrase inhibitor that is used to treat idiopathic intracranial hypertension, glaucoma, and epilepsy. The use of acetazolamide has not been recommended for pregnant women because of reported teratogenic risks. Congenital malformations, such as ectrodactyly, syndactyly, cleft lip/palate, and retarded incisor teeth development, have been reported in experimental animals. However, tooth agenesis due to the use of acetazolamide has not been reported yet. Oligodontia is a severe type of tooth agenesis involving six or more congenitally missing teeth. The causes of oligodontia are attributed to environmental factors, such as irradiation, drugs, trauma, tumors, infection, genetic factors, or a combination. There is no credible evidence of undesirable effects of acetazolamide use in human pregnancy. However, we report a case of a 12-year-old Saudi boy who was exposed to maternal acetazolamide (1,000 mg/day) for treatment of idiopathic intracranial hypertension before pregnancy, during the first trimester, and throughout the pregnancy. This treatment might have resulted in some congenital malformations, such as ectrodactyly, syndactyly, and oligodontia.

Background Alcohol-related mortality and morbidity among women has increased over recent decades, especially in areas of higher deprivation. Pre-pregnancy alcohol use is associated with continued consumption in pregnancy. We assessed whether general population alcohol consumption patterns were reflected among pregnant women in two Scottish areas with different deprivation levels. Methods Cross-sectional study in two health boards (HB1, lower deprivation levels, n = 274; HB2, higher deprivation levels, n = 236), using face-to-face 7-day Retrospective Diary estimation of peri-conceptual and mid-pregnancy alcohol consumption. Results A greater proportion of women in HB2 (higher deprivation area) sometimes drank peri-conceptually, but women in HB1 (lower deprivation area) were more likely to drink every week (49.6 vs 29.7%; p < 0.001) and to exceed daily limits (6 units) at least once each week (32.1 vs 14.8%; p < 0.001). After pregnancy recognition, consumption levels fell sharply, but women in HB2 were more likely to drink above recommended daily limits (2 units) each week (2.5 vs 0.0%; p < 0.05). However, women in HB1 were more likely to drink frequently. Women with the highest deprivation scores in each area drank on average less than women with the lowest deprivation scores. Conclusions Heavy episodic and frequent consumption was more common in the lower deprivation area, in contrast with general population data. Eliciting a detailed alcohol history at the antenatal booking visit, and not simply establishing whether the woman is currently drinking, is essential. Inconsistent messages about the effects of alcohol in pregnancy may have contributed to the mixed picture we found concerning peri-conceptual and mid-pregnancy alcohol consumption.

This study aimed to explore evidence for the influence of air pollution on the risk of birth defects in China and contribute to establish prevention strategies.We conducted a retrospective cohort study in Anqing city, Eastern China, from 2010 to 2012. Binary logistic regression models were used to estimate odds ratios (ORs) per 10 μg/m3 change for SO2, NO2, and PM10.For continuous exposure to SO2 (10 μg/m increase), the adjusted OR for birth defects is 1.20 [95% confidence interval (95% CI) 1.09 to 1.29] in the preconception. A 10 μg/m increase in SO2 (adjusted OR 1.26, 95% CI 1.15 to 1.36) during the second trimester is strongly associated with birth defects. No associations have been observed for NO2 and PM10.The results suggested that exposure to ambient SO2 during pregnancy may increase the risk of birth defects.

The problem of carcinogenic risk in offsprings of individuals exposed to radiation is challenging and insufficiently studied. In that there are no evaluations of the interaction between radiation and non-radiation factors. The aim of the study was the analysis of interaction of preconceptive radiation exposure and parents' onco-pathology in cancer mortality in offsprings (F1) of workers (fathers) of the Mayak Production Association exposed to a wide range of doses of radiation over a year prior conception. The number of offspring is 8191 individuals (4180 men and 4011 women). The analysis was performed with the use of fourfold table and eightfold tables. The interaction offactors was estimated on the base of the additive and multiplicative models. The studied factors were independent. The odds ratio (OR) of cancer mortality in the offspring with parents' oncopathology (1.43) was insignificant. OR of cancer mortality in preconceptive radiation exposure in a dose over 110 mGy and without parents' onco-pathology was 2.61 (1.52-4.49), and in their combination--3.86 (1.93-7.71). Index of synergism of preconceptive radiation exposure and parents' onco-patholog in the rise of carcinogenic risk in the offspring was 1.34 and the character of their interaction was multiplicative. Thus, for the first time there was established the interaction between radiation and non-radiation factors in the synergism sort in the increase of carcinogenic risk in the offspring of people exposed to radiation.

background: Obesity and related conditions, notably subfertility, are increasingly prevalent. Paternal influences are known to influence offspring health outcome, but the impact of paternal obesity and subfertility on the reproductive health of subsequent generations has been overlooked. methods: A high-fat diet (HFD) was used to induce obesity but not diabetes in male C57Bl6 mice, which were subsequently mated to normal-weight females. First-generation offspring were raised on a control diet and their gametes were investigated for signs of subfertility. Second-generation offspring were generated from both first generation sexes and their gametes were similarly assessed. results: We demonstrate a HFD-induced paternal initiation of subfertility in both male and female offspring of two generations of mice. Furthermore, we have shown that diminished reproductive and gamete functions are transmitted through the first generation paternal line to both sexes of the second generation and via the first generation maternal line to second-generation males. Our previous findings that founder male obesity alters the epigenome of sperm, could provide a basis for the developmental programming of subfertility in subsequent generations. conclusions: This is the first observation of paternal transmission of diminished reproductive health to future generations and could have significant implications for the transgenerational amplification of subfertility observed worldwide in humans.

Developmental exposure to polychlorinated biphenyls (PCBs) disrupts reproduction in animals. Human data are lacking. We measured PCBs in preserved mothers' serum samples collected during 1960-1963, 1-3 days after their daughters' birth. We recorded time to pregnancy (TTP) in 289 daughters 28-31 years later. PCB congeners 187, 156, and 99 in mother's serum were associated with longer TTP in their daughters while PCB congeners 105, 138 and 183 were associated shorter TTP. Probability of pregnancy fell by 38% (95% CI 17-53%) and infertility was higher (30% not pregnant after 13 cycles versus 11% not pregnant after 13 cycles) among women whose mothers had a higher proportion of PCB congeners associated with longer TTP (75th percentile versus 25th percentile). This study demonstrates, for the first time, that developmental exposure to PCBs may disrupt pregnancy in humans.

Radiation and other agents can cause germ-cell mutations in animal systems. No human germ-cell mutagen has been identified, but this does not mean that human germ-cells are not vulnerable to mutagenesis. There has been particular concern about the possible health effects on offspring following parental preconception exposure to ionizing radiation-both occupational and therapeutic. A strong association with preconception radiation exposure in the fathers of the cases was found in a case-control study of young people with leukaemia living near the Sellafield nuclear plant in the UK. Subsequent studies of workers occupationally exposed to ionizing radiation have failed to confirm these findings. No statistically significant effects have been reported from studies of possible indicators of germ-cell mutagenesis in the A-bomb survivors. Studies of offspring of cancer survivors who receive radiotherapy and mutagenic chemotherapy have found no evidence of germ-cell mutagenesis. Failure to detect human germ-cell mutagenic agents may be a consequence of inadequate study sizes or insufficiently sensitive laboratory techniques.

Background Paternal preconception risk factors such as smoking, exposure to environmental substances, medication use, overweight and advanced age correlate with the occurrence of malformations and birth defects in the offspring. Nonetheless, the prevalence of risk factors for adverse pregnancy outcomes in the male population has been scarcely investigated and no report on preconception interventions targeting prospective fathers is available. We conducted a web-based survey to measure the prevalence of paternal preconception risk factors for adverse pregnancy outcomes in an Italian population of Internet users. Methods Prospective or expectant fathers were enrolled during a four-week period through two of the main Italian web-sites dedicated to preconception, pregnancy, childhood and family care. Participants filled in a web questionnaire regarding preconception risk factors for adverse pregnancy outcomes. Logistic regression analysis was used to explore the predictors of paternal preconception risk factors. Results We enrolled 131 prospective and 205 expectant fathers. More than half of the total participants used medications during the preconception period, 35 % were smokers and 8 % were obese. Exposure to environmental substances was declared by almost 20 % of the participants, with the group including pesticides/herbicides/professional paints being the most prevalent. More than a half of the study sample included men aged over 35 years. According to the multivariate analysis, smoking and exposure to environmental toxics were less frequent among individuals with a university degree (respectively: OR = 0.52; 95 % CI 0.32–0.84; OR = 0.52; 95 % CI 0.29–0.93). Paternal obesity and medication use in the preconception period were not associated with any of the independent variables. Conclusions The prevalence of preconception risk factors among male population should not be neglected when planning preconception interventions, confirming that preconception health must be focused on the couple, rather than on women only. Electronic supplementary material The online version of this article (doi:10.1186/s12978-016-0156-6) contains supplementary material, which is available to authorized users.

The congenital malformation gastroschisis has a genetic disposition in the inbred mouse strain HLG/Zte. It is increased after preconceptional irradiation of males or females. Radiation exposures during the meiotic stages are most efficient. This malformation can also be induced by ionising radiation when the exposure takes place during the preimplantation period especially during the zygote stage. This latter effect can be transmitted to the next mouse generation. Other macroscopically visible or skeletal malformations are not significantly induced under these experimental conditions. These latter malformations are increased by radiation exposures during major organogenesis. The mechanisms for the development of the effects are different. Radiation exposure of the mouse zygote (1 to 3 hours p.c.) also leads to the induction of genomic instability in skin fibroblasts of the fetus. This phenomenon also occurs in a mouse strain (C57BL/6J) which is not susceptible to radiation-induced gastroschisis during the preimplantation period. The genomic instability is transmitted to the next mouse generation. During genomic instability chromatide breaks are dominating as in non-exposed cells. With respect to "spontaneous" malformations gastroschisis is dominating in HLG/Zte mice. Late radiation effects seem to have similar patterns as observed in non-exposed subjects, however, the rates are increased after irradiation.

Attempts to determine or to select what kind of person or people to bring into existence are controversial. This is particularly true of “negative selection” or “selecting against” a certain type of person—that is, the attempt to prevent a person of a certain type, or people of that type, from existing. Virtually everyone agrees that some instances of negative selection are objectionable—for example, that selection against healthy people would be wrong, particularly if this were combined with positive selection of people with serious diseases. But some people believe that all negative selection is objectionable and therefore that all “selection for existence,” whether positive or negative, is objectionable. For if negative selection is objectionable, it seems to follow that positive selection is as well, since the attempt to bring a person of a certain type into existence is simultaneously an attempt not to bring into existence a person who is not of that type. In short, positive selection is implicitly negative as well. Why would someone believe that, for example, the attempt to avoid having a child with Tay-Sachs disease is objectionable? The reasons given vary but usually appeal to the idea that to decide that certain people ought not to exist is to discriminate against people of a certain type on the basis of values that are contested or not universally valid. I will not discuss the view that all selection is wrong, which is in any case the view of only a small minority. Most people believe that some forms of se

Neurodevelopmental models of schizophrenia that identify longitudinal precursors of illness have been of great heuristic importance focusing most etiologic research over the past two decades. These models have varied considerably with respect to specificity and timing of hypothesized genetic and environmental 'hits', but have largely focused on insults to prenatal brain development. With heritability around 80%, nongenetic factors impairing development must also be part of the model, and any model must also account for the wide range of age of onset. In recent years, longitudinal brain imaging studies of both early and adult (to distinguish from late ie elderly) onset populations indicate that progressive brain changes are more dynamic than previously thought, with gray matter volume loss particularly striking in adolescence and appearing to be an exaggeration of the normal developmental pattern. This supports an extended time period of abnormal neurodevelopment in schizophrenia in addition to earlier 'lesions'. Many subtle cognitive, motor, and behavioral deviations are seen years before illness onset, and these are more prominent in early onset cases. Moreover, schizophrenia susceptibility genes and chromosomal abnormalities, particularly as examined for early onset populations (ie GAD1, 22q11DS), are associated with premorbid neurodevelopmental abnormalities. Several candidate genes for schizophrenia (eg dysbindin) are associated with lower cognitive abilities in both schizophrenic and other pediatric populations more generally. Postmortem human brain and developmental animal studies document multiple and diverse effects of developmental genes (including schizophrenia susceptibility genes), at sequential stages of brain development. These may underlie the broad array of premorbid cognitive and behavioral abnormalities seen in schizophrenia, and neurodevelopmental disorders more generally. Increased specificity for the most relevant environmental risk factors such as exposure to prenatal infection, and their interaction with susceptibility genes and/or action through phase-specific altered gene expression now both strengthen and modify the neurodevelopmental theory of schizophrenia.

Introduction Pregnancy is associated with several hormonal changes which influence the developing fetus. Variations in maternal endogenous hormones and prepregnancy use of hormonal preparations have been linked to asthma and allergy in the offspring, but findings are inconsistent. We plan to undertake a systematic review to synthesise the evidence on the association between endogenous and exogenous maternal sex hormones and the risk of asthma and allergy in the offspring. Methods and analysis We will search Medline, Embase, Cochrane Library, Institute of Scientific Information Web of Science, Cumulative Index of Nursing and Allied Health, Scopus, Google Scholar, Allied and Complementary Medicine Database, Global Health, Psychological Information (PsycINFO), Centre for Agriculture and Bioscience (CAB) International and WHO Global Health Library from inception until 2016 to identify relevant studies on the topic. Additional studies will be identified by searching databases of proceedings of international conferences, contacting international experts in the field and searching the references cited in identified studies. We will include analytical epidemiological studies. Two researchers will independently screen identified studies, undertake data extraction and assess risk of bias in eligible studies, while a third reviewer will arbitrate any disagreement. We will use the Effective Public Health Practice Project tool to assess the risk of bias in the studies. We will perform a random-effects meta-analysis to synthesise the evidence. We will use the Grading of Recommendations Assessment, Development and Evaluation approach to rate the strength and quality of the overall evidence with respect to each outcome. Ethics and dissemination Ethical approval is not required since the study is a systematic review of published literature. Our findings will be reported in a peer-reviewed scientific journal. PROSPERO registration number CRD42016048324

The research was carried out in 60 days old posterity of female rats which suffer chronic alcohol-induced liver injury. In this work we studied motivational element of sexual behavior under conditions of "barrier" experiment. Intensity of sexual motivational behavior was estimated by the change of activity near the barrier, under which there was a receptive oestrous female. The appearance of sexual activity with the animals under experiment was estimated in the experiment of direct interaction of sexual partners. It was found, that "alcoholic" animals have the symptoms of malfunction of sexual motivation formation. The experiment shows that males which had mothers with chronic alcohol-induced hepatobiliary system injury have the deviations of sexual behavior display. These deviations show the weak form of sexual behavior induction of "alcoholic" males that can be the result of nervous system disorders.

Features of the existential organization of a bioelectric activity of a brain at posterity from rats with a lateral injury of the brain were investigated. The EEG analysis revealed in one month animals significantly increased the proportion of advanced and lagging decrease in the activity of the right frontal derivation towards the right occipital region. Change between structural ties in terms of the rats were correlated with the severity of behavioral disorders in the test "open field" (OF). The most significant change in the existential organization of a bioelectrical activity (the reduction of synchronous communications between the frontal derivations) recorded in rats with severe conduct disorder compared with animals of the same groups, in which the behavior was not significantly different from the norm. The violation of the behavior in the test OF was accompanied by a decrease in synchronous activity between the left frontal and right occipital region or the decline in the anticipatory activity in the right frontal region in relation to the right occipital region. By maintaining the integrity of the behavior of these parameters were increased in comparison with an intact control.

To examine pregnancy outcomes in the partners of male patients with inflammatory joint disease who were or were not exposed to disease-modifying antirheumatic drugs (DMARDs) before conception compared with the outcomes in reference subjects from the general population.Linkage of data from a longitudinal observational study of patients with inflammatory joint disease (the Norwegian Disease-Modifying Antirheumatic Drug [NOR-DMARD] registry study) and the Medical Birth Registry of Norway (MBRN) enabled a comparison of pregnancy outcomes in the partners of men with inflammatory joint disease. Outcomes of pregnancies in which the father was exposed to DMARDs within 12 weeks of conception and those in which the father was never exposed to DMARDs were analyzed separately and compared with the outcomes in reference subjects. Potential associations between DMARD exposure and adverse pregnancy outcomes were assessed by logistic regression analysis.A total of 1,796 men with inflammatory joint disease were associated with 2,777 births in the MBRN. In 110 of these births, the father had been exposed to DMARDs within 12 weeks before conception, and in 230 births the father had never been exposed to DMARDs before conception. The DMARDs (monotherapy or combination treatment) to which the fathers were exposed most frequently within 12 weeks of conception were methotrexate (n = 49), sulfasalazine (n = 17), and tumor necrosis factor inhibitors (n = 57). Neither adverse pregnancy outcomes nor occurrence of congenital malformations differed between patients and reference subjects in either group.Preconception paternal exposure to DMARDs was not associated with an increase in adverse pregnancy outcomes. Importantly, no increased risk of congenital malformations was observed.

Adverse condition of rat development during the prenatal period (rearing by mother survived brain injury) or during the early post-natal period (cross fostering), causes impairment of motor behavior and a lipid turnover in adult rats. Such rats under severe stress showed decrease of adaptation (as expressed or low indexes of motor impellent behavior and lipid metabolism) in comparison with rats that were grown up by own mother. The psychoemotional stress caused the most expressed deficient behavior in males that were grown up by mothers with brain injury (decrease in serum level of HC and HDL and depressively - similar behavior).

The authors proved relationship between congenital abnormalities in children and influence of chemical factors (methanol and formaldehyde production) on the parents. Higher risk of congenital abnormalities was seen: PR = 5.6 (chi2 = 3.54; p = 0.00001), EF = 0.95. These disorders could be connected with work conditions--exceeded MAC for methanol 3.9-fold, that for formaldehyde--2.4-fold.

Background Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene. Methods We examined DNA from umbilical cord blood leukocytes from 79 newborns, born between July 2005 and November 2006 at Duke University Hospital, Durham, NC. Their mothers participated in the Newborn Epigenetics Study (NEST) during pregnancy. Parental characteristics were obtained via standardized questionnaires and medical records. DNA methylation patterns at two DMRs were analyzed by bisulfite pyrosequencing; one DMR upstream of IGF2 (IGF2 DMR), and one DMR upstream of the neighboring H19 gene (H19 DMR). Multiple regression models were used to determine potential associations between the offspring's DNA methylation patterns and parental obesity before conception. Obesity was defined as body mass index (BMI) ≥30 kg/m2. Results Hypomethylation at the IGF2 DMR was associated with paternal obesity. Even after adjusting for several maternal and newborn characteristics, we observed a persistent inverse association between DNA methylation in the offspring and paternal obesity (β-coefficient was -5.28, P = 0.003). At the H19 DMR, no significant associations were detected between methylation patterns and paternal obesity. Our data suggest an increase in DNA methylation at the IGF2 and H19 DMRs among newborns from obese mothers, but a larger study is warranted to further explore the potential effects of maternal obesity or lifestyle on the offspring's epigenome. Conclusions While our small sample size is limited, our data indicate a preconceptional impact of paternal obesity on the reprogramming of imprint marks during spermatogenesis. Given the biological importance of imprinting fidelity, our study provides evidence for transgenerational effects of paternal obesity that may influence the offspring's future health status.

Background Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene. Methods We examined DNA from umbilical cord blood leukocytes from 79 newborns, born between July 2005 and November 2006 at Duke University Hospital, Durham, NC. Their mothers participated in the Newborn Epigenetics Study (NEST) during pregnancy. Parental characteristics were obtained via standardized questionnaires and medical records. DNA methylation patterns at two DMRs were analyzed by bisulfite pyrosequencing; one DMR upstream of IGF2 (IGF2 DMR), and one DMR upstream of the neighboring H19 gene (H19 DMR). Multiple regression models were used to determine potential associations between the offspring's DNA methylation patterns and parental obesity before conception. Obesity was defined as body mass index (BMI) ≥30 kg/m2. Results Hypomethylation at the IGF2 DMR was associated with paternal obesity. Even after adjusting for several maternal and newborn characteristics, we observed a persistent inverse association between DNA methylation in the offspring and paternal obesity (β-coefficient was -5.28, P = 0.003). At the H19 DMR, no significant associations were detected between methylation patterns and paternal obesity. Our data suggest an increase in DNA methylation at the IGF2 and H19 DMRs among newborns from obese mothers, but a larger study is warranted to further explore the potential effects of maternal obesity or lifestyle on the offspring's epigenome. Conclusions While our small sample size is limited, our data indicate a preconceptional impact of paternal obesity on the reprogramming of imprint marks during spermatogenesis. Given the biological importance of imprinting fidelity, our study provides evidence for transgenerational effects of paternal obesity that may influence the offspring's future health status.

SENTIERI Project (Mortality study of residents in Italian polluted sites) studies mortality of residents in 44 sites of national interest for environmental remediation (Italian polluted sites, IPSs). A development of the Project is the investigation of adverse reproductive effects. This issue is of the utmost importance in the field of environmental epidemiology, both in analytical studies and in surveillance activity. An environmental factor can be at play either as a preconception mutagen (maternal or paternal exposure) or as a postconceptional teratogen. The US-Agency for Toxic Substances and Disease Registry (ATSDR) and the US-Environmental Protection Agency (USEPA), indicate as a priority the study of congenital anomalies (CA) and reproductive disorders. The choice of congenital anomalies to be included in the study is mainly based on the results of the evaluation of the epidemiological evidence completed for SENTIERI Project. The epidemiological knowledge on congenital anomalies in polluted sites is lacking, therefore main groups of CA will also be included for descriptive purposes. Data on CA are produced by seven registers located in Italy, either in regional or sub-regional areas, which are included in the National Committee of Congenital Malformations Registers hosted by the National Center for Rare Diseases at Istituto Superiore di Sanità. The study periods are: a) 1995-2002 (1996-2002 for the Region Campania), namely the same years as SENTIERI mortality study; b) for the years 2003-2008 different time windows will be chosen on the basis of data availability in single registers. Registers of CA are active in 16 out of 44 polluted sites included in SENTIERI, for a total of 119 municipalities. In each polluted site the number of expected cases for each CA will be estimated from the prevalence at birth of the same anomaly as from regional registers active in the polluted site at study. For a description of SENTIERI, refer to the 2010 Supplement of EpidemiologyPrevention devoted to the Project.

We reviewed the evidence for three theories of how preconceptional psychosocial stress could act as a contributing determinant of excess preterm birth risk among African American women: early life developmental plasticity and epigenetic programming of adult neuroendocrine systems; blunting, weathering, or dysfunction of neuroendocrine and immune function in response to chronic stress activation through the life course; individuals' adoption of risky behaviors such as smoking as a response to stressful stimuli.Basic science, clinical, and epidemiologic studies indexed in MEDLINE and Web of Science databases on preconceptional psychosocial stress, preterm birth and race were reviewed.Mixed evidence leans towards modest associations between preconceptional chronic stress and preterm birth (for example common odds ratios of 1.2-1.4), particularly in African American women, but it is unclear whether this association is causal or explains a substantial portion of the Black-White racial disparity in preterm birth. The stress-preterm birth association may be mediated by hypothalamic-pituitary-adrenal axis dysfunction and susceptibility to bacterial vaginosis, although these mechanisms are incompletely understood. Evidence for the role of epigenetic or early life programming as a determinant of racial disparities in preterm birth risk is more circumstantial.Preconceptional stress, directly or in interaction with host genetic susceptibility or infection, remains an important hypothesized risk factor for understanding and reducing racial disparities in preterm birth. Future studies that integrate adequately sized epidemiologic samples with measures of stress, infection, and gene expression, will advance our knowledge and allow development of targeted interventions.

Aim Observation of identical genetic changes in leukemia cells from monozygotic twin pairs has provided evidence for the in utero single clonal origin hypothesis of leukemia, with intraplacental metastasis the basis for concordance. Investigation of this rare mixed lineage leukemia ( MLL ) cytogenetic abnormality aims to provide further evidence of the genetic changes that underpin this aggressive form of leukemia in infants. Method The clinical features of a monozygotic infant twin pair with acute lymphoblastic leukemia (ALL) are reported. Banded chromosomal analysis and fluorescent in situ hybridization were used for cytogenetic characterization of the leukemic cells. Immunophenotype was determined by flow cytometry and polymerase chain reaction was used to determine the presence of FLT3 -D835/I836 and FLT3 -internal tandem duplication (ITD) mutations. Results The twins were seven weeks of age at diagnosis. Both had cytogenetic evidence for the t(1;11)(p32;q23) translocation. Trisomy X was present in a subpopulation of cells in one twin. Immunophenotypic profile at diagnosis was consistent with B precursor ALL (CD19, CD24, CD33 positive, weak CD13 positivity, CD10 negative) and both were negative for FLT3 -D835/I836 and FLT3 -ITD mutations. Conclusions This is the first report of monochorionic monozygotic twins harboring the t(1;11)(p32;q23) translocation. Identification of this rare translocation in both twins, indicates a common stem line and provides further evidence for the intrauterine monoclonal origin for infant ALL with concordance explained by the shared circulation. Genetic diversity was observed in a subpopulation of cells from one twin at diagnosis. We must now utilize the sophisticated molecular biology tools available to capture changes at the genome-wide level to gain further insight into the complex events contributing to MLL leukemogenesis in infants.

Objective To evaluate the effect of pregestational metformin administration on abortion risk in polycystic ovary syndrome (PCOS) patients. Design Systematic review and meta-analysis. Setting Academic Department of Obstetrics and Gynecology in Italy. Patient(s) Women affected by PCOS receiving pregestational metformin. Intervention(s) Systematic review of randomized controlled trials (RCTs) published up to June 2008 and subsequent meta-analysis. Main Outcome Measure(s) Abortion rate. Result(s) Seventeen RCTs were included in the final analysis. Overall, no effect of the metformin administration was detected on the abortion risk. No statistically significant effect of metformin on the abortion risk was observed in any comparison when subgrouping the RCTs according to received treatment. Conclusion(s) Metformin has no effect on the abortion risk in PCOS patients when administered before pregnancy.

Consumption of fish contaminated with polychlorinated biphenyls (PCBs) and prenatal PCB serum concentrations have been associated with a longer time-to-pregnancy (TTP). However, the relationship between preconception serum PCBs concentrations and TTP has not been previously studied.Eighty-three women (contributing 442 menstrual cycles) planning pregnancies completed daily diaries regarding menstruation, intercourse, home pregnancy test results, and reported use of alcohol and cigarettes. TTP denoted the number of observed menstrual cycles required for pregnancy. Preconception blood specimens underwent toxicologic analysis for 76 PCB congeners via gas chromatography with electron capture; serum lipids were quantified with enzymatic methods. A priori, PCB congeners were summed into a total and three groupings-estrogenic, anti-estrogenic and other-and entered into discrete analogs of Cox models with time-varying covariates to estimate fecundability odds ratios (FOR) and corresponding 95% confidence intervals (CIs).Estrogenic and anti-estrogenic PCB concentrations (ng/g serum) conferred reduced FORs in fully adjusted models (0.32; 95% CI 0.03, 3.90 and 0.01: 95% CI0.00, 1.99, respectively). Reduced FORs (0.96) were observed for alcohol consumption standardized to a 28-day menstrual cycle in the same adjusted model (FOR = 0.96; 95% CI 0.93, 1.00).These data suggest that environmental exposures including those amenable to change, such as alcohol consumption, may impact female fecundity. The findings are sensitive to model specification and PCB groupings, underscoring the need to further assess the impact of chemical mixtures on sensitive reproductive outcomes, such as TTP, especially in the context of lifestyle factors which are amenable to change, thereby improving reproductive health.

The majority of patients with inflammatory bowel disease (IBD) are affected during their peak reproductive years.1 While initial concerns focus on attaining a durable remission and avoiding the side effects of medications, once in remission the focus often shifts to the effect of disease and the medications used to treat it on fertility and the ability to conceive a healthy child. This paper summarises the existing literature on the effects of ulcerative colitis (UC) and Crohn’s disease (CD) and the medications used to treat it on fertility and pregnancy outcomes. Patients are naturally concerned about passing their disease on to their offspring. Unfortunately, family history is the strongest predictor for developing IBD. If one parent is affected, the risks of the offspring developing IBD are 2–13 times higher than in the general population.2,3 One study estimated that the risks of IBD in first degree relatives of probands with UC and CD were 1.6% and 5.2%, respectively, values that were even higher in the Jewish population.4 If both parents have IBD, the risk of their offspring developing IBD over their lifetime was estimated to be 36%.5 Several studies suggest that breastfeeding may be protective against the development of IBD in the infant. In a meta-analysis of 17 studies, the eight highest quality studies showed a pooled odds ratio of 0.45 (0.26, 0.79) for CD and 0.56 (0.38, 0.81) for UC.6 However, these were not mothers who had IBD themselves. Infertility is defined as the diminished ability or the inability to conceive and have offspring. It is also defined in specific terms as failure to conceive after a year of regular intercourse without contraception. In general, women with CD appear to have similar fertility rates to the general population. Older referral centre studies estimated infertility rates …

Contains fulltext : 51670.pdf (Publisher’s version ) (Closed access) Despite being one of the most common congenital defects in boys, the etiology of hypospadias remains largely unknown. In this case-referent study, we evaluated a wide spectrum of potential risk factors for hypospadias. Cases were identified from the hospital information system, and referents were recruited through the parents of the cases. Both parents of cases and referents completed written questionnaires that they received through the mail. Logistic regression analyses were used to assess the independent contribution of different factors to the risk of hypospadias. The final database included 583 cases and 251 referents. Hypospadias more often occurred in children whose father had hypospadias (OR=9.7; 95%CI: 1.3-74.0) and in children with a low birth weight (OR=2.3; 95%CI: 1.2-4.2). Indications for elevated risks were found when mothers were DES-daughters (OR=3.5; 95%CI: 0.8-15.6), fathers were subfertile (OR=1.8; 95%CI: 0.7-4.5), the parents had undergone fertility treatment (OR=2.3; 95%CI: 0.9-5.8), and in twin or triplet pregnancies (OR=2.0; 95%CI: 0.8-5.1). Maternal use of iron supplements (OR=2.2; 95%CI: 0.8-6.0), maternal smoking (OR=1.5; 95%CI: 1.0-2.4), paternal prescriptive drug use (OR=2.6; 95%CI: 1.1-6.6), and paternal exposure to pesticides (OR=2.1; 95%CI: 0.6-7.1) during the 3 months immediately prior to conception or in the first trimester of pregnancy also appeared to increase the risk of hypospadias. The associations found in this study support the hypothesis that genetic predisposition, placental insufficiency, and substances that interfere with natural hormones play a role in the etiology of hypospadias.