Prenatal diethylstilbestrol (DES) exposure is associated with increased risk of hormonally mediated cancers and other medical conditions. We evaluated the association between DES and risk of pancreatic cancer and pancreatic disorders, type 2 diabetes, and gallbladder disease, which may be involved with this malignancy. Our analyses used follow-up data from the US National Cancer Institute DES Combined Cohort Study. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age, sex, cohort, body mass index, smoking, and alcohol for the association between prenatal DES exposure and type 2 diabetes, gallbladder disease (mainly cholelithiasis), pancreatic disorders (mainly pancreatitis), and pancreatic cancer among 5667 exposed and 3315 unexposed individuals followed from 1990 to 2017. Standardized incidence rate (SIR) ratios for pancreatic cancer were based on age-, race-, and calendar year-specific general population cancer incidence rates. In women and men combined, the hazards for total pancreatic disorders and pancreatitis were greater in the prenatally DES exposed than the unexposed (HR = 11, 95% CI 2.6–51 and HR = 7.0, 95% CI 1.5–33, respectively). DES was not associated overall with gallbladder disease (HR = 1.2, 95% CI 0.88–1.5) or diabetes (HR = 1.1, 95% CI 0.9–1.2). In women, but not in men, DES exposure was associated with increased risk of pancreatic cancer compared with the unexposed (HR: 4.1, 95% CI 0.84–20) or general population (SIR: 1.9, 95% CI 1.0–3.2). Prenatal DES exposure may increase the risk of pancreatic disorders, including pancreatitis in women and men. The data suggested elevated pancreatic cancer risk in DES-exposed women, but not in exposed men.

The Ethiopian great famine was one of the severe forms of global famines ever documented in Africa as well as in the recent history of the world. Earlier famine studies, as natural experiments, had tested the association between prenatal famine exposure and the metabolic syndrome and reported heterogeneous findings. Hence, this study aimed at evaluating the effects of prenatal exposure to the 1983–1985 Ethiopian great famine on the metabolic syndrome in adults. Self-reported birth date and age of the study subjects were used to classify the status of famine exposure. The International Diabetes Federation criterion was used to assess the metabolic syndrome. Multivariable logistic regression models were fitted to examine relationship between prenatal famine exposure and the metabolic syndrome. The findings showed that, adjusted for covariates, adults who had prenatal exposure to famine were 2·94 times more likely to develop the metabolic syndrome compared with non-exposed groups (adjusted OR (AOR) 2·94, 95 % CI 1·66, 5·27). More specifically, famine exposure during prenatal life was associated with increased waist circumference (AOR 2·27 cm, 95 % CI 0·28, 4·26), diastolic blood pressure (AOR 2·47 mmHg, 95 % CI 0·84, 4·11), TAG (AOR 0·20 mmol/l, 95 % CI 0·10, 0·28) and fasting blood glucose (AOR 0·24 mmol/l, 95 % CI 0·04, 0·43) compared with the control groups. Higher proportion of the metabolic syndrome, risky anthropometric and dyslipidaemic parameters were observed among exposed groups. This finding adds further evidence on fetal origin of adult diseases hypothesis. The finding may imply that one potential means of preventing adulthood metabolic syndrome is to optimise maternal nutrition during pregnancy.

Prenatal exposure to mercury in utero causes abnormal foetal growth and adverse outcomes. DNA methylation is currently considered a possible mechanism through which this occurs. However, few studies have investigated the association between prenatal exposure to mercury and DNA methylation in detail. This study aimed to clarify the relationship between prenatal exposure to total mercury (Hg) and DNA methylation and its associations with sex-specific characteristics in male and female offspring. In a birth cohort study known as the Chiba study of Mother and Child Health, the DNA methylation status in cord tissue and Hg concentrations in cord serum were examined. A total of 67 participants (27 males and 40 females) were analysed based on Spearmanʼs correlations, adjusted by a false discovery rate of the sex of each offspring. Only one methylated locus was positively correlated with Hg concentrations in cord serum in male offspring, but not in female offspring, and was annotated to the haloacid dehalogenase-like hydrolase domain-containing protein 1 (HDHD1) gene on chromosome X. This locus was located in the intron of the HDHD1 gene body and is a binding site for the zinc finger protein CCCTC-binding factor. One of the other loci, located in HDHD1, was highly methylated in the group with higher mercury concentrations, and this locus was in the gene body of HDHD1. Our results suggest that prenatal exposure to Hg might affect the epigenetic status of male foetuses.

Prenatal exposure to persistent organic pollutants (POPs) has been associated with the development of metabolic syndrome-related diseases in offspring. According to epidemiological studies, father’s transmission of environmental effects in addition to mother’s can influence offspring health. Moreover, maternal prenatal dietary folic acid (FA) may beneficially impact offspring health. The objective is to investigate whether prenatal FA supplementation can overcome the deleterious effects of prenatal exposure to POPs on lipid homeostasis and inflammation in three generations of male rat descendants through the paternal lineage. Female Sprague-Dawley rats (F0) were exposed to a POPs mixture (or corn oil) +/− FA supplementation for 9 weeks before and during gestation. F1 and F2 males were mated with untreated females. Plasma and hepatic lipids were measured in F1, F2, and F3 males after 12-h fast. Gene expression of inflammatory cytokines was determined by qPCR in epididymal adipose tissue. In F1 males, prenatal POPs exposure increased plasma lipids at 14 weeks old and hepatic lipids at 28 weeks old and prenatal FA supplementation decreased plasma total cholesterol at 14 weeks old. Prenatal POPs exposure decreased plasma triglycerides at 14 weeks old in F2 males. No change was observed in inflammatory markers. Our results show an impact of the paternal lineage on lipid homeostasis in rats up to the F2 male generation. FA supplementation of the F0 diet, regardless of POPs exposure, lowered plasma cholesterol in F1 males but failed to attenuate the deleterious effects of prenatal POPs exposure on plasma and hepatic lipids in F1 males.

Studies examining associations between fetal serotonin reuptake inhibitor (SRI) exposure and child autism spectrum disorder (ASD) diagnoses or delayed language remain mixed and rarely prospectively follow children or employ gold-standard assessments. We prospectively followed a cohort of mother–child dyads from pregnancy through early elementary school (N = 178), and obtained maternal and alternate–caregiver ratings of behaviors related to ASD (N = 137), as well as direct, gold-standard assessments of child ASD symptoms and pragmatic language among dyads who experienced prenatal depression and either took SRIs or were medication free during pregnancy (N = 44). Prenatal SRI exposure was related to maternal ratings of ASD-related behaviors (β = 0.24 95% confidence interval; CI [0.07, 0.48]), and, among boys, alternative caregiver ratings (males-only β = 0.28 95% CI [0.02, 0.55], females-only β = −0.21 95% CI [–0.63, 0.08]). However, results of our direct assessments suggest an association between SRI exposure and reduced pragmatic language scores (β = –0.27, 95% CI [–0.53, –0.01], but not ASD (Autism Diagnostic Observation Schedule β = 0.14 95% CI [–0.15, 0.41]; Social Responsiveness Scale β = 0.08 95% CI [–0.25, 0.40]). These discrepancies point to issues regarding how ASD is assessed, and the possibility that SRIs may be more strongly associated with language or other broader behaviors that coincide with ASD. Larger prospective studies that incorporate thorough, gold-standard assessments of ASD, language, and other ASD-related behaviors are needed.

Elevated levels of organochlorines (OC) have been reported in Inuit populations in the Arctic. We hypothesized that prenatal exposure to a Canadian Arctic OC mixture adversely affects male reproductive function and health with age. Sprague–Dawley female rats (F0) were gavaged with an environmentally relevant concentration of an Arctic OC mixture or corn oil (Control) during mating with untreated males until parturition (F1 litters). After postnatal day (PND) 90, the weights of the OC F1 males differed dramatically relative to Controls (P<0.05; n=10) and they exhibited respiratory distress. Except for possible thinning of the alveolar barrier, histological observation of the lungs revealed no apparent pathology to explain the respiratory distress. At PND 365, OC F1 males had reduced relative reproductive organ weights and lower sperm quality than Controls (P<0.05). At PND 90, OC F1 males were subfertile (P<0.05), but were infertile at PND 365. In conclusion, environmentally relevant prenatal OC exposure reduced reproductive function and health in aging male rats, providing new insight into the effects of early-life exposures to these contaminants.

The current measures of cognitive functioning in adulthood do not indicate a long-term association with prenatal exposure to the Dutch famine. However, whether such association emerges in China is poorly understood. We aimed to investigate the potential effect of prenatal exposure to the 1959–1961 Chinese famine on adult cognitive impairment. We obtained data from the Second National Sample Survey on Disability implemented in thirty-one provinces in 2006, and restricted our analysis to 387 093 individuals born in 1956–1965. Cognitive impairment was defined as intelligence quotient (IQ) score under 70 and IQ of adults was evaluated by the Wechsler Adult Intelligence Scale – China Revision. Famine severity was defined as excess death rate. The famine impact on adult cognitive impairment was estimated by difference-in-difference models, established by examining the variations of famine exposure across birth cohorts. Results show that compared with adults born in 1956–1958, those who were exposed to Chinese famine during gestation (born in 1959–1961) were at greater risk of cognitive impairment in the total sample. Stratified analyses showed that this effect was evident in males and females, but only in rural, not in urban areas. In conclusion, prenatal exposure to famine had an enduring deleterious effect on risk of cognitive impairment in rural adults.

Reproductive effects from phthalate exposure have been documented mostly in animal studies. This study explored the association between prenatal exposure to phthalate metabolites, anogenital distance and penile measurements in male newborns in Toluca, State of Mexico. A total of 174 pregnant women provided urine samples for phthalate analysis during their last prenatal visit, and the 73 who gave birth to male infants were included in the study. The 73 male newborns were weighed and measured using standardized methods after delivery. After adjusting for creatinine and supine length at birth, significant inverse associations were observed between an index of prenatal exposure to total phthalate exposure and the distance from the anus to anterior base of the penis (β = −0.191 mm per 1 μg/l, P = 0.037), penile width (β = −0.0414, P = 0.050) and stretched length (β = −0.2137, P = 0.034); prenatal exposure to mono-2-ethylhexyl phthalate exposure was associated with a reduction in the stretched length of the penis (β = −0.2604, P = 0.050). Human exposure to phthalates is a public health concern, and the system most vulnerable to its potential effects seems to be the immature male reproductive tract.

Fetal exposure to caffeine is associated with adverse pregnancy outcomes. Animal and human studies suggest that caffeine may have effects on the developing reproductive system. Here we report on mothers’ smoking, coffee and alcohol use, recorded during pregnancy, and semen quality in sons in the age group of 38–47 years. Subjects were a subset of the Child Health and Development Studies, a pregnancy cohort enrolled between 1959 and 1967 in the Kaiser Foundation Health Plan near Oakland, California. In 2005, adult sons participated in a follow-up study (n = 338) and semen samples were donated by 196 participants. Samples were analyzed for sperm concentration, motility and morphology according to the National Cooperative Reproductive Medicine Network (Fertile Male Study) Protocol. Mean sperm concentration was reduced by approximately 16 million sperms for sons with high prenatal exposure (5 cups of maternal coffee use per day) compared with unexposed sons (P-value for decreasing trend = 0.09), which translates to a proportionate reduction of 25%. Mean percent motile sperm decreased by approximately 7 points (P-value = 0.04), a proportionate decline of 13%, and mean percent sperm with normal morphology decreased by approximately 2 points (P-value = 0.01), a proportionate decline of 25%. Maternal cigarette and alcohol use were not associated with son's semen quality. Adjusting for son's contemporary coffee, alcohol and cigarette use did not explain the maternal associations. Findings for son's coffee intake and father's prenatal coffee, cigarette and alcohol use were non-significant and inconclusive. These results contribute to the evidence that maternal coffee use during pregnancy may impair the reproductive development of the male fetus.

Aim – This study examines the relationship between prenatal cocaine exposure and parent-reported child behavior problems at age 7 years. Methods – Data are from 407 African-American children (210 cocaine-exposed, 197 non-cocaine-exposed) enrolled prospectively at birth in a longitudinal study on the neurodevelopmental consequences of in utero exposure to cocaine. Prenatal cocaine exposure was assessed at delivery through maternal self-report and bioassays (maternal and infant urine and infant meconium). The Achenbach Child Behavior Checklist (CBCL), a measure of childhood externalizing and internalizing behavior problems, was completed by the child's current primary caregiver during an assessment visit scheduled when the child was seven years old. Results – Structural equation and GLM/GEE models disclosed no association linking prenatal cocaine exposure status or level of cocaine exposure to child behavior (CBCL Externalizing and Internalizing scores or the eight CBCL sub-scale scores). Conclusions – This evidence, based on standardized ratings by the current primary caregiver, fails to support hypothesized cocaine-associated behavioral problems in school-aged children with in utero cocaine exposure. A next step in this line of research is to secure standardized ratings from other informants (e.g., teachers, youth self-report).

Declaration of Interest: This research was conducted in the context of an ongoing longitudinal study funded by the National Institutes of Health National Institute on Drug Abuse (R01 DA 06556). Support was also provided by a NIDA career development award (K01 DA 16720), a NIDA research training award (T32 DA 07292), the General Clinical Research Center (MOI RR 16587), and the Health Foundation of South Florida.

Maternal seafood intake is of great health interest since it constitutes an important source of n-3 fatty acids, but provides also an important pathway for fetal exposure to Hg. The objective of the present study was to determine associations between Hg contamination and both maternal seafood consumption and fetal growth in French pregnant women. Pregnant women included in the ‘EDEN mother–child’ cohort study answered FFQ on their usual diet in the year before and during the last 3 months of pregnancy, from which frequencies of seafood intake were evaluated. Total hair-Hg level was determined for the first 691 included women. Associations between Hg level, seafood intake and several neonatal measurements were studied using linear regressions adjusted for confounding variables. The median Hg level for mothers was 0·52 μg/g. Maternal seafood intake was associated with Hg level (r 0·33; P < 0·0001). There was no association between Hg level and fetal growth in the whole sample of women, except for an early negative relationship with biparietal diameter. A positive association was found between seafood intake and fetal growth in overweight women only which remained unchanged after adjustment for Hg level (birth weight: +101 g for a difference of 1 sd in seafood consumption; P = 0·008). Although seafood intake was associated with Hg contamination in French pregnant women, the contamination level was low. There was no consistent association between Hg level and fetal growth. Taking into account Hg level did not modify associations between seafood intake and fetal growth.

The aim of the present systematic review was to evaluate the influence of early life exposure (maternal and childhood) to peanuts and the subsequent development of sensitisation or allergy to peanuts during childhood. Studies were identified using electronic databases and bibliography searches. Studies that assessed the impact of non-avoidance compared with avoidance or reduced quantities of peanuts or peanut products on either sensitisation or allergy to peanuts, or both outcomes, were eligible. Six human studies were identified: two randomised controlled trials, two case–control studies and two cross-sectional studies. In addition, published animal and mechanistic studies, relevant to the question of whether early life exposure to peanuts affects the subsequent development of peanut sensitisation, were reviewed narratively. Overall, the evidence reviewed was heterogeneous, and was limited in quality, for example, through lack of adjustment for potentially confounding factors. The nature of the evidence has therefore hindered the development of definitive conclusions. The systematic review of human studies and narrative expert-led reviews of animal studies do not provide clear evidence to suggest that either maternal exposure, or early or delayed introduction of peanuts in the diets of children, has an impact upon subsequent development of sensitisation or allergy to peanuts. Results from some animal studies (and limited evidence from human subjects) suggest that the dose of peanuts is an important mediator of peanut sensitisation and tolerance; low doses tend to lead to sensitisation and higher doses tend to lead to tolerance.