Objective
To assess the association between in utero exposure to either diethylstilbestrol (DES) or an oral contraceptive in pregnancy and offspring obesity.
Methods
Using data from the Collaborative ...Perinatal Project (1959‐1974), a multicenter prospective study of pregnant women and their offspring, we examined overweight or obesity among 34,419 children with height and weight data at age 7 years. Generalized linear models to estimate the adjusted odds ratio (aOR) for overweight or obesity (≥85th percentile) or obesity (≥95th percentile) in the offspring according to exposure during different months of pregnancy were used.
Results
Oral contraceptive use during pregnancy was positively associated with offspring overweight or obesity and obesity. The magnitude of association was strongest in the first 2 months of pregnancy for obesity (aOR 2.0, 95% CI: 1.1, 3.7). DES use was also associated with offspring overweight or obesity and obesity, with the association being strongest for exposure beginning between months 3 and 5 (e.g., for exposure beginning in months 3‐4, the aOR for obesity was 2.8, 95% CI: 1.3, 6.3).
Conclusions
Pharmacologic sex hormone use in pregnancy may be associated with childhood obesity. Whether contemporary, lower dose oral contraceptive formulations are similarly associated with increased risk of childhood obesity is unclear.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The widespread use of organophosphate (OP) pesticides has resulted in ubiquitous exposure in humans, primarily through their diet. Exposure to OP pesticides may have adverse health effects, including ...neurobehavioral deficits in children. The optimal design of new studies requires data on the reliability of urinary measures of exposure. In the present study, urinary concentrations of six dialkyl phosphate (DAP) metabolites, the main urinary metabolites of OP pesticides, were determined in 120 pregnant women participating in the Generation R Study in Rotterdam. Intra-class correlation coefficients (ICCs) across serial urine specimens taken at <18, 18-25, and >25 weeks of pregnancy were determined to assess reliability. Geometric mean total DAP metabolite concentrations were 229 (GSD 2.2), 240 (GSD 2.1), and 224 (GSD 2.2) nmol/g creatinine across the three periods of gestation. Metabolite concentrations from the serial urine specimens in general correlated moderately. The ICCs for the six DAP metabolites ranged from 0.14 to 0.38 (0.30 for total DAPs), indicating weak to moderate reliability. Although the DAP metabolite levels observed in this study are slightly higher and slightly more correlated than in previous studies, the low to moderate reliability indicates a high degree of within-person variability, which presents challenges for designing well-powered epidemiological studies.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Perfluorooctane sulfonic acid (PFOS) is a ubiquitous environmental contaminant. Most people in developed countries have detectable serum concentrations. Lower birth weight has been associated with ...serum PFOS in studies world-wide, many of which have been published only recently.
To facilitate a causal assessment of the birth weight and PFOS association, we updated previous meta-analyses of the association and employed a method that facilitated inclusion of all available data in one analysis. Our analysis was based on observations from 29 studies.
The random effects summary was -3.22 g/ng/ml (95% confidence interval CI = -5.11, -1.33). In a subgroup analysis stratified by when in pregnancy the PFOS concentration was measured, the summary for the early group was -1.35 (95% CI = -2.33, -0.37) and for the later group was -7.17 (95% CI = -10.93, -3.41). In a meta-regression model including a term for timing of blood draw, the intercept was slightly positive but essentially zero (0.59 g/ng/ml, 95% CI = -1.94, 3.11). In other words, the model indicated that when blood was drawn at the very beginning of pregnancy, there was essentially no relation of birth weight to PFOS. The results from the subgroup analyses differed from those from the model because the average gestational age at blood draw in the early group was 14 weeks, when bias would still be expected. A stronger inverse association in Asian studies was not completely explained by their blood draws being from later in pregnancy.
The evidence was weakly or not supportive of a causal association.
Concerns about reproductive and developmental health risks of exposure to organophosphate (OP) pesticides, phthalates, and bisphenol A (BPA) among the general population are increasing. Six dialkyl ...phosphate (DAP) metabolites, 3,5,6-trichloro-2-pyridinol (TCPy), BPA, and fourteen phthalate metabolites were measured in 10 pooled urine samples representing 110 pregnant women who participated in the Norwegian Mother and Child Birth Cohort (MoBa) study in 2004. Daily intakes were estimated from urinary data and compared with reference doses (RfDs) and daily tolerable intakes (TDIs). The MoBa women had a higher mean BPA concentration (4.50
μg/L) than the pregnant women in the Generation R Study (Generation R) in the Netherlands and the National Health and Nutrition Examination Survey (NHANES) in the United States. The mean concentration of total DAP metabolites (24.20
μg/L) in MoBa women was higher than that in NHANES women but lower than that in Generation R women. The diethyl phthalate metabolite mono-ethyl phthalate (MEP) was the dominant phthalate metabolite in all three studies, with the mean concentrations of greater than 300
μg/L. The MoBa and Generation R women had higher mean concentrations of mono-n-butyl phthalate (MnBP) and mono-isobutyl phthalate (MiBP) than the NHANES women. The estimated average daily intakes of BPA, chlorpyrifos/chlorpyrifos-methyl and phthalates in MoBa (and the other two studies) were below the RfDs and TDIs. The higher levels of metabolites in the MoBa participants may have been from intake via pesticide residues in food (organophosphates), consumption of canned food, especially fish/seafood (BPA), and use of personal care products (selected phthalates).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
An association between increased serum concentrations of perfluoroalkyl substances (PFAS) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and early menopause has been reported ...(Knox et al., 2011; Taylor et al., 2014). This association may be explained by the fact that women who underwent menopause no longer excrete PFAS through menstruation. Our objective was to assess how much of the epidemiologic association between PFAS and altered timing of menopause might be explained by reverse causality. We extended a published population life-stage physiologically-based pharmacokinetic (PBPK) model of PFOS and PFOA characterized by realistic distributions of physiological parameters including age at menopause. We then conducted Monte Carlo simulations to replicate the Taylor population (Taylor et al., 2014) and the Knox population (Knox et al., 2011). The analysis of the simulated data overall showed a pattern of results that was comparable to those reported in epidemiological studies. For example, in the simulated Knox population (ages 42–51) the odds ratio (OR) for menopause in the fifth quintile of PFOA compared to those in the first quintile was 1.33 (95% CI 1.26–1.40), whereas the reported OR was 1.4 (95% CI 1.1–1.8). Using our model structure, a substantial portion of the associations reported can be explained by pharmacokinetics.
•Blood PFAS concentrations increase in menopausal women because of reduced loss in menses.•The PFAS Monte Carlo PBPK model reproduces epidemiological population characteristics.•Pharmacokinetics explain a substantial portion of the associations between serum PFAS and onset of menopause.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background
Normal brain development is dependent on maternal, fetal and neonatal thyroid function. Measuring neonatal thyroid‐stimulating hormone (TSH) 48‐72 hours after birth screens for congenital ...hypothyroidism, allowing early treatment to avoid serious impairment. However, even within sub‐clinical ranges, disrupted thyroid homeostasis during brain development has been linked to adverse neurodevelopmental outcomes, including attention‐deficit/hyperactivity disorder (ADHD).
Objectives
To estimate the association between neonatal TSH below threshold for potential congenital hypothyroidism and subsequent ADHD diagnosis using a population‐based birth cohort.
Methods
Children with a diagnosis of ADHD in the Norwegian Mother, Father and Child Cohort Study (MoBa) were identified through linkage with the Norwegian Patient Registry using ICD‐10 codes for hyperkinetic disorders. The study included 405 ADHD cases and 1,092 controls (born 2003‐2008) with available neonatal TSH concentrations below 10 mU/L (cut‐off for potential congenital hypothyroidism) measured in dried blood spots sampled 48‐72 hours after birth.
Results
In multivariable, quintile models the relationship appeared to follow a U‐shaped pattern with elevated odds ratios (OR) at lower and higher TSH levels. Among children with TSH in the lowest quintile, odds of ADHD was approximately 1.5‐fold higher than children in the middle quintile (OR 1.60, 95% CI 1.09, 2.34), which was driven by substantially elevated risk among girls, with no association among boys (Pinteraction = 0.02; girls OR 3.10, 95% CI 1.53, 6.30; boys OR 1.16, 95% CI 0.73, 1.84).
Conclusions
ADHD risk appeared to be elevated among newborns with low TSH levels (i.e. with hyperthyroid status), and this association was mainly found among girls. Because our findings are suggestive of increased risk at very low TSH concentrations, where analytical accuracy is low, future studies should employ highly sensitive assays capable of accurate quantitation at very low concentrations. Also, larger studies are needed to investigate these associations at higher neonatal TSH concentrations where data are more widely distributed.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Brominated flame retardants (BFRs) have been in widespread use in a vast array of consumer products since the 1970s. The metabolites of some BFRs show a structural similarity to thyroid hormones and ...experimental animal studies have confirmed that they may interfere with thyroid hormone homeostasis. A major concern has been whether intrauterine exposure to BFRs may disturb thyroid homeostasis since the fetal brain is particularly susceptible to alterations in thyroid hormones. However, few reports on newborns have been published to date.
To evaluate the association between BFRs and neonatal thyroid-stimulating hormone (TSH).
We studied six polybrominated diphenyl ethers (PBDEs) measured in milk samples from 239 women who were part of the “Norwegian Human Milk Study” (HUMIS), 2003–2006. Hexabromocyclododecane (HBCD) and BDE-209 were measured in a subset of the women (193 and 46 milk samples, respectively). The milk was sampled at a median of 33 days after delivery. TSH was measured in babies three days after delivery as part of the routine national screening program for early detection of congenital hypothyroidism. Additional information was obtained through the Medical Birth Registry and questionnaires to the mothers.
The PBDE concentrations in human milk in Norway were comparable to concentrations reported from other European countries and Asia, but not the US and Canada where levels are approximately one order of higher magnitude. We observed no statistically significant associations between BDE-47, 99, 153, 154, 209 and HBCD in human milk and TSH in models adjusted for possible confounders and other environmental toxicants including polychlorinated biphenyls (PCBs).
We did not observe an association between TSH and exposure to HBCD and PBDEs within the exposure levels observed.
► Exposure to brominated flame retardants may disturb thyroid homeostasis. ► We examined the association between eight BFRs in human milk and TSH measured three days after delivery. ► We did not observe an association between TSH and exposure to HBCD and PBDEs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
An association between serum levels of two perfluoroalkyl substances (PFAS) and delayed age at menarche was reported in a cross-sectional study of adolescents. Because perfluorooctanoic acid (PFOA) ...and perfluorooctane sulfonate (PFOS) have half-lives of years, growth dilution and the development of a new route of excretion (menstruation) could account for some or all of the reported association.
To assess how much of the epidemiologic association between PFAS and delayed menarche can be explained by the correlation of growth and maturation with PFAS body burden.
We developed a Monte Carlo (MC) physiologically-based pharmacokinetic (PBPK) model of PFAS to simulate plasma PFAS levels in a hypothetical female population aged 2 to 20years old. Realistic distributions of physiological parameters as well as timing of growth spurts and menarche were incorporated in the model. The association between PFAS level and delayed menarche in the simulated data was compared with the reported association.
The prevalence of menarche, distributions of age-dependent physiological parameters, and quartiles of serum PFAS concentrations in the simulated subjects were comparable to those reported in the epidemiologic study. The delay of menarche in days per natural log increase in PFAS concentrations in the simulated data were about one third as large as the observed values.
The reported relationship between PFAS and age at menarche appears to be at least partly explained by pharmacokinetics rather than a toxic effect of these substances.
•Ability to simulate longitudinal trends in blood biomarkers in early life•Kinetic variation contributed to the association between PFAS and age at menarche.•MC-PBPK modeling can enhance interpretation of epidemiological associations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A higher body mass index (BMI) has been positively associated with the rate of excretion of di-2-ethylhexyl phthalate (DEHP) metabolites in urine in data from the National Health and Nutrition ...Examination Survey (NHANES), suggesting an association between DEHP exposure and BMI. The association, however, may be due to the association between body mass maintenance and higher energy intake, with higher energy intake being accompanied by a higher intake of DEHP. To examine this hypothesis, we ran a Monte Carlo simulation with a DEHP physiologically-based pharmacokinetic (PBPK) model for adult humans. A realistic exposure sub-model was used, which included the relation of body weight to energy intake and of energy intake to DEHP intake. The model simulation output, when compared with urinary metabolite data from NHANES, supported good model validity. The distribution of BMI in the simulated population closely resembled that in the NHANES population. This indicated that the simulated subjects and DEHP exposure model were closely aligned with the NHANES population of interest. In the simulated population, the ordinary least squares regression coefficient for log(BMI) as a function of log(DEHP nmol/min) was 0.048 (SE 0.001), as compared with the reported value of 0.019 (SE 0.005). In other words, given our model structure, the higher energy intake in the overweight and obese, and the concomitant higher DEHP exposure, describes the reported relationship between BMI and DEHP.
•Intake of di-2-ethylhexyl phthalate has been associated with higher body mass index.•People with higher body mass index have a higher energy intake.•Higher energy intake is associated with higher intake of DEHP.•We simulated these relationships using a pharmacokinetic model of NHANES subjects.•Higher energy intake in the overweight and obese describes the BMI-DEHP association.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background: Perfluorinated compounds are ubiquitous pollutants; epidemiologic data suggest they may be associated with adverse health outcomes, including subfecundity. We examined subfecundity in ...relation to 2 perfluorinated compounds—perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). Methods: This case-control analysis included 910 women enrolled in the Norwegian Mother and Child Cohort Study in 2003 and 2004. Around gestational week 17, women reported their time to pregnancy and provided blood samples. Cases consisted of 416 women with a time to pregnancy greater than 12 months, considered subfecund. Plasma concentrations of perfluorinated compounds were analyzed using liquid chromatography—mass spectrometry. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for each pollutant quartile using logistic regression. Estimates were further stratified by parity. Results: The median plasma concentration of PFOS was 13.0 ng/mL (interquartile range IQR = 10.3—16.6 ng/mL) and of PFOA was 2.2 ng/mL (IQR = 1.7—3.0 ng/mL). The relative odds of subfecundity among parous women was 2.1 (95% CI = 1.2—3.8) for the highest PFOS quartile and 2.1 (1.0—4.0) for the highest PFOA quartile. Among nulliparous women, the respective relative odds were 0.7 (0.4—1.3) and 0.5 (0.2—1.2). Conclusion: Previous studies suggest that the body burden of perfluorinated compounds decreases during pregnancy and lactation through transfer to the fetus and to breast milk. Afterward, the body burden may increase again. Among parous women, increased body burden may be due to a long interpregnancy interval rather than the cause of a long time to pregnancy. Therefore, data from nulliparous women may be more informative regarding toxic effects of perfluorinated compounds. Our results among nulliparous women did not support an association with subfecundity.
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BFBNIB, CMK, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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