Background: Epigenetic modifications, such as DNA methylation, due to in utero exposures may play a critical role in early programming for childhood and adult illness. Maternal smoking is a major risk factor for multiple adverse health outcomes in children, but the underlying mechanisms are unclear.Objective: We investigated epigenome-wide methylation in cord blood of newborns in relation to maternal smoking during pregnancy.Methods: We examined maternal plasma cotinine (an objective biomarker of smoking) measured during pregnancy in relation to DNA methylation at 473,844 CpG sites (CpGs) in 1,062 newborn cord blood samples from the Norwegian Mother and Child Cohort Study (MoBa) using the Infinium HumanMethylation450 BeadChip (450K).Results: We found differential DNA methylation at epigenome-wide statistical significance (p-value < 1.06 × 10–7) for 26 CpGs mapped to 10 genes. We replicated findings for CpGs in AHRR, CYP1A1, and GFI1 at strict Bonferroni-corrected statistical significance in a U.S. birth cohort. AHRR and CYP1A1 play a key role in the aryl hydrocarbon receptor signaling pathway, which mediates the detoxification of the components of tobacco smoke. GFI1 is involved in diverse developmental processes but has not previously been implicated in responses to tobacco smoke.Conclusions: We identified a set of genes with methylation changes present at birth in children whose mothers smoked during pregnancy. This is the first study of differential methylation across the genome in relation to maternal smoking during pregnancy using the 450K platform. Our findings implicate epigenetic mechanisms in the pathogenesis of the adverse health outcomes associated with this important in utero exposure.

Perfluorooctane sulfonate and perfluorooctanoic acid are perfluorinated compounds (PFCs) widely distributed in the environment. Previous studies of PFCs and birth weight are equivocal. The authors examined this association in the Norwegian Mother and Child Cohort Study (MoBa), using data from 901 women enrolled from 2003 to 2004 and selected for a prior case-based study of PFCs and subfecundity. Maternal plasma samples were obtained around 17 weeks of gestation. Outcomes included birth weight z scores, preterm birth, small for gestational age, and large for gestational age. The adjusted birth weight z scores were slightly lower among infants born to mothers in the highest quartiles of PFCs compared with infants born to mothers in the lowest quartiles: for perfluorooctane sulfonate, β = -0.18 (95% confidence interval: -0.41, 0.05) and, for perfluorooctanoic acid, β = -0.21 (95% confidence interval: -0.45, 0.04). No clear evidence of an association with small for gestational age or large for gestational age was observed. Perfluorooctane sulfonate and perfluorooctanoic acid were each associated with decreased adjusted odds of preterm birth, although the cell counts were small. Whether some of the associations suggested by these findings may be due to a noncausal pharmacokinetic mechanism remains unclear.

Recent data suggest that prenatal exposure to p,p'-DDE may reduce height and increase body mass index (BMI) in childhood, thus potentially raising the risk of adult health problems. The association between prenatal DDE exposure and growth was evaluated in 788 boys from Chiapas, an area of Mexico where DDT was recently used. The median DDE levels in maternal serum at birth (2002)(2003) were 2.7 μg/g lipid. 2,633 measurements of height (cm) and weight (kg) were obtained in [2004][2005]. The median age of the children during follow-up was 18 months (quartiles 14 and 22 months). Height and body mass index (kg/m 2 ) were age-standardized and expressed as standard deviation scores (SDS). Multivariate random-effect models for longitudinal data were fitted and predicted height and BMI SDS were estimated from the adjusted models. Overall, associations between prenatal DDE level and height or BMI SDS at any given age were not observed. For example, the predicted values showed that children with the highest exposure (DDE: >9.00 μg/g) compared to those least exposed (DDE: < 3.01 μg/g) grew similarly and they had a BMI SDS similar to the referent group. The results do not support the prior findings of an association of DDE exposure with childhood height or BMI.

Background: In some previous studies, prenatal exposure to persistent organochlorines such as 1,1,-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p´-DDE), polychlorinated biphenyls (PCBs), and hexachlorobenzene (HCB) has been associated with higher body mass index (BMI) in children.Objective: Our goal was to evaluate the association of maternal serum levels of β-hexachlorocyclohexane (β-HCH), p,p´-DDE, dichlorodiphenyltrichloroethane (p,p´-DDT), dieldrin, heptachlor epoxide, HCB, trans-nonachlor, oxychlordane, and PCBs with offspring obesity during childhood.Methods: The analysis was based on a subsample of 1,915 children followed until 7 years of age as part of the U.S. Collaborative Perinatal Project (CPP). The CPP enrolled pregnant women in 1959–1965; exposure levels were measured in third-trimester maternal serum that was collected before these organochlorines were banned in the United States. Childhood overweight and obesity were defined using age- and sex-specific cut points for BMI as recommended by the International Obesity Task Force.Results: Adjusted results did not show clear evidence for an association between organochlorine exposure and obesity; however, a suggestive finding emerged for dieldrin. Compared with those in the lowest quintile (dieldrin, < 0.57 μg/L), odds of obesity were 3.6 (95% CI: 1.3, 10.5) for the fourth and 2.3 (95% CI: 0.8, 7.1) for the highest quintile. Overweight and BMI were unrelated to organochlorine exposure.Conclusions: In this population with relatively high levels of exposure to organochlorines, no clear associations with obesity or BMI emerged.Citation: Cupul-Uicab LA, Klebanoff MA, Brock JW, Longnecker MP. 2013. Prenatal exposure to persistent organochlorines and childhood obesity in the U.S. Collaborative Perinatal Project. Environ Health Perspect 121:1103–1109; http://dx.doi.org/10.1289/ehp.1205901

The insecticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) is still used for disease control in some areas, resulting in high levels of human exposure. The main degradation product of DDT is 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), an antiandrogen. In animal experiments, in utero exposure to DDE decreases anogenital distance in male offspring. In these models, anogenital distance serves as a measure of fetal androgen action. The authors designed the present study to examine the hypothesis that in utero exposure to DDE decreases anogenital distance in newborn human males. A cross-sectional study of 781 newly delivered male infants was conducted in 2002-2003 in Chiapas, Mé xico, where DDT had recently been used for malaria control. Measurements of anogenital distance and penile dimensions were taken, and a sample of the mother's blood was drawn. In this population, the range of serum DDE levels was large (0.8-398 lg/liter). The authors, using two-sided tests, found no evidence that exposure in utero to DDE was related to reduced androgen action as reflected by anogenital distance or penile dimensions at birth. If DDE has important antiandrogenic action in humans, it may be manifest only at higher levels of exposure or via effects on other outcomes.

Development of the perineum as well as the external genitalia is determined by dihydrotestosterone, resulting in a greater anogenital distance (AGD) in males than females. In animal experiments with hormonally active agents, anogenital distance is used as a bioassay of fetal androgen action. Use of anogenital distance in human studies has been rare. Because anogenital distance has been an easy-to-measure, sensitive outcome in animal studies, we developed an anthropometric protocol for measurement of anogenital distance in human males. In this paper we describe the method for measurement of three anogenital distances, their reliability, and an assessment of predictors for each in the context of an epidemiological study. We compare the reliabilities and predictors to those for stretched penis length and penis width. A cross-sectional study of 781 newly delivered male infants was conducted in 2002-03 in Chiapas, Mexico. Replicate measures were obtained on nearly all subjects. The reliability of the measures of anogenital distance (0.82-0.91) were higher than for stretched penis length (0.78) and width (0.75). Birthweight and gestational length were more strongly related to anogenital distance than to penis length. Anogenital distance was not related to penis length (r = 0.03). Our large study clearly shows that AGD can be measured well in newborn males, and that the measurements were more reliable than those of penis length. Whether AGD measures in humans relate to clinically important outcomes, however, remains to be determined, as does its utility as a measure of androgen action in epidemiological studies.

Background: Environmental factors influencing the developmental origins of health and disease need to be identified and investigated. In utero exposure to tobacco smoke has been associated with obesity and a small increase in blood pressure in children; however, whether there is a corresponding increased risk of conditions such as diabetes and hypertension during adulthood remains unclear.Objective: Our goal was to assess the association of self-reported in utero exposure to tobacco smoke with the prevalence of obesity, hypertension, type 2 diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM) in women 14–47 years of age.Methods: We conducted a cross-sectional analysis of the Norwegian Mother and Child Cohort Study, which enrolled pregnant women in Norway from 1999 thorough 2008. Exposure to tobacco smoke in utero (yes vs. no) was ascertained on the baseline questionnaire (obtained at ~ 17 weeks’ gestation); the outcomes were ascertained from the Medical Birth Registry of Norway and the questionnaire. Our analysis included 74,023 women.Results: Women exposed to tobacco smoke in utero had 1.53 times the odds of obesity [95% confidence interval (CI): 1.45, 1.61] relative to those unexposed, after adjusting for age, education, and personal smoking. After further adjustment for body mass index, the odds ratio for hypertension was 1.68 (95% CI: 1.19, 2.39); for T2DM 1.14 (95% CI: 0.79, 1.65); and for GDM 1.32 (95% CI: 1.10, 1.58) among exposed compared with unexposed.Conclusions: Exposure to tobacco smoke in utero was associated with obesity, hypertension, and GDM in adult women. The possibility that the associations were attributable to unmeasured confounding cannot be excluded.

BackgroundHigher levels of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), the major degradation product of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT), have been related to shorter duration of breast-feeding in previous studies. If DDE truly shortens lactation, this has public health importance regarding infant mortality and the use of DDT for malaria control.ObjectiveOur aim was to assess the relationship of maternal DDE concentrations with length of subsequent lactation.MethodsWe conducted a relatively large study in a highly exposed area of Mexico. We followed 784 mother–son pairs to determine length of lactation. DDE and DDT were measured in maternal serum obtained within a day of delivery. We fit proportional hazard models with and without stratifying by previous breast-feeding, because an association of DDE with duration of lactation among those who breast-fed previously could be attributed to a noncausal mechanism.ResultsCompared with those with DDE concentrations ≤ 3.00 μg/g, the adjusted hazard ratios of weaning according to DDE category were, for concentrations 3.01–6.00 μg/g, 1.27 [95% confidence interval (CI), 1.04–1.55]; for concentrations 6.01–9.00 μg/g, 1.23 (95% CI, 0.92–1.63); and for concentrations > 9.00 μg/g, 1.17 (95% CI, 0.92–1.49). The corresponding ratios for women who previously breast-fed were 1.40 (95% CI, 1.06–1.87); 1.91 (95% CI, 1.24–2.93); and 1.76 (95% CI, 1.22–2.53). Those for women who had not breast-fed previously were 1.14 (95% CI, 0.86–1.52); 0.90 (95% CI, 0.61–1.31); and 0.91 (95% CI, 0.66–1.26).ConclusionsData from our relatively large study in a highly exposed area of Mexico did not support the hypothesis that exposure to DDE shortens length of lactation. The association seen in women who previously breast-fed was likely attributed to a noncausal mechanism. Nonetheless, whether DDT has other important adverse effects on humans is still an open question.