Associations of bisphenol and phthalate exposure and anti-Müllerian hormone levels in women of reproductive age

Background:In women, exposure to endocrine disrupting chemicals might accelerate the depletion of the ovarian reserve and might be associated with accelerative reproductive aging and fertility. We examined the longitudinal associations of exposure to bisphenols and phthalates with anti-Müllerian hormone concentrations.Methods:Pregnant women of 18 years or older that resided in Rotterdam between 2002 and 2006 were eligible for participation in this longitudinal prospective cohort study. We measured urinary bisphenol and phthalate concentration at three time-points in pregnancy among 1405 women, of whom 1322 women had serum Anti-Müllerian Hormone (AMH) measurements 6 and/or 9 years postpartum. We performed linear regression models to assess the association of urinary bisphenol and phthalate metabolites with AMH after 6 and 9 years, and linear mixed-effect model to assess the association with AMH over time. Models were adjusted for sociodemographic and lifestyle factors. Findings: In our multivariable linear regression models we observed associations of higher urinary pregnancy-averaged mono-isobutyl phthalate (mIBP), mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP), and monobenzyl phthalate (mBzBP) with lower serum AMH after both 6 and 9 years. However, these associations did not remain after adjustment for multiple testing. No significant associations of bisphenol A with AMH were present in our study sample. In our linear mixed-effects models, higher mIBP, mono-(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mEOHP, and mBzBP were associated with lower overall AMH levels (differences −0.07 (95% CI −0.13, −0.02), −0.09 (−0.15, −0.02), −0.08 (95% CI −0.14, −0.02), and −0.08 (−0.13, −0.03) μg/L per doubling in mIBP, mEHHP, mEOHP, and mBzBP respectively) (all False Discovery Rate adjusted p-values &lt; 0.05). Interpretation: We identify decreases in indices of ovarian reserve in relationship to prenatal phthalate exposures. Studies are needed replicating our results among large multi-ethnic non-pregnant populations and assessing transgenerational effects of exposure on ovarian reserve. Funding: This study was supported by the Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organisation for Health Research and Development, the European Research Council, the Dutch Heart Foundation, the Dutch Diabetes Foundation, the European Union's Horizon 2020 Research and Innovation Program, the National Institutes of Health, Ansh Labs Webster, and the Royal Netherlands Academy of Arts and Sciences.</p

Fetal bisphenol and phthalate exposure and early childhood growth in a New York City birth cohort

Background: Exposure to endocrine-disrupting chemicals such as bisphenols and phthalates during pregnancy may disrupt fetal developmental programming and influence early-life growth. We hypothesized that prenatal bisphenol and phthalate exposure was associated with alterations in adiposity through 4 years. This associations might change over time. Methods: Among 1091 mother–child pairs in a New York City birth cohort study, we measured maternal urinary concentrations of bisphenols and phthalates at three time points in pregnancy and child weight, height, and triceps and subscapular skinfold thickness at ages 1, 2, 3, and 4 years. We used linear mixed models to assess associations of prenatal individual and grouped bisphenols and phthalates with overall and time-point-specific adiposity outcomes from birth to 4 years. Results: We observed associations of higher maternal urinary second trimester total bisphenol and bisphenol A concentrations in pregnancy and overall child weight between birth and 4 years only (Beta 0.10 (95 % confidence interval 0.04, 0.16) and 0.07 (0.02, 0.12) standard deviation score (SDS) change in weight per natural log increase in exposure), We reported an interaction of the exposures with time, and analysis showed associations of higher pregnancy-averaged mono-(2-carboxymethyl) phthalate with higher child weight at 3 years (0.14 (0.06, 0.22)), and of higher high-molecular-weight phthalate, di-2-ethylhexyl phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate, mono-(2-carboxymethyl) phthalate, and mono-(2-ethylhexyl) phthalate with higher child weight at 4 years (0.16 (0.04, 0.28), 0.15 (0.03, 0.27), 0.19 (0.07, 0.31), 0.16 (0.07, 0.24), 0.11 (0.03, 0.19)). Higher pregnancy-averaged high-molecular-weight phthalate, di-2-ethylhexyl phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, and mono-2(ethyl-5-oxohexyl) phthalate concentrations were associated with higher child BMI at 4 years (0.20 (0.05, 0.35), 0.20 (0.05, 0.35), 0.22 (0.06, 0.37), 0.20 (0.05, 0.34), 0.20 (0.05, 0.34)). For skinfold thicknesses, we observed no associations. Discussion: This study contributes to the evidence suggesting associations of prenatal exposure to bisphenols and high-molecular-weight phthalates on childhood weight and BMI.</p

Fetal bisphenol and phthalate exposure and early childhood growth in a New York City birth cohort

Background: Exposure to endocrine-disrupting chemicals such as bisphenols and phthalates during pregnancy may disrupt fetal developmental programming and influence early-life growth. We hypothesized that prenatal bisphenol and phthalate exposure was associated with alterations in adiposity through 4 years. This associations might change over time. Methods: Among 1091 mother–child pairs in a New York City birth cohort study, we measured maternal urinary concentrations of bisphenols and phthalates at three time points in pregnancy and child weight, height, and triceps and subscapular skinfold thickness at ages 1, 2, 3, and 4 years. We used linear mixed models to assess associations of prenatal individual and grouped bisphenols and phthalates with overall and time-point-specific adiposity outcomes from birth to 4 years. Results: We observed associations of higher maternal urinary second trimester total bisphenol and bisphenol A concentrations in pregnancy and overall child weight between birth and 4 years only (Beta 0.10 (95 % confidence interval 0.04, 0.16) and 0.07 (0.02, 0.12) standard deviation score (SDS) change in weight per natural log increase in exposure), We reported an interaction of the exposures with time, and analysis showed associations of higher pregnancy-averaged mono-(2-carboxymethyl) phthalate with higher child weight at 3 years (0.14 (0.06, 0.22)), and of higher high-molecular-weight phthalate, di-2-ethylhexyl phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate, mono-(2-carboxymethyl) phthalate, and mono-(2-ethylhexyl) phthalate with higher child weight at 4 years (0.16 (0.04, 0.28), 0.15 (0.03, 0.27), 0.19 (0.07, 0.31), 0.16 (0.07, 0.24), 0.11 (0.03, 0.19)). Higher pregnancy-averaged high-molecular-weight phthalate, di-2-ethylhexyl phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, and mono-2(ethyl-5-oxohexyl) phthalate concentrations were associated with higher child BMI at 4 years (0.20 (0.05, 0.35), 0.20 (0.05, 0.35), 0.22 (0.06, 0.37), 0.20 (0.05, 0.34), 0.20 (0.05, 0.34)). For skinfold thicknesses, we observed no associations. Discussion: This study contributes to the evidence suggesting associations of prenatal exposure to bisphenols and high-molecular-weight phthalates on childhood weight and BMI.</p

Fetal Organophosphate Pesticide Exposure and Child Adiposity Measures at 10 Years of Age in the General Dutch Population

BACKGROUND: Fetal exposure to organophosphate (OP) pesticides might lead to fetal metabolic adaptations, predisposing individuals to adverse metabolic profiles in later life. OBJECTIVE: We examined the association of maternal urinary OP pesticide metabolite concentrations in pregnancy with offspring body mass index (BMI) and fat measures at 10 years of age. METHODS: Between 2002 and 2006, we included 642 mother–child pairs from the Generation R Study, a population-based prospective cohort study in Rotterdam, the Netherlands. We measured maternal urinary concentrations of OP pesticide metabolites, namely, dialkyl phosphates, including three dimethyl and three diethyl phosphates in early-, mid-and late-pregnancy. At 10 years of age, child total and regional body fat and lean mass were measured through dual energy X-ray absorptiometry, and abdominal and organ fat through magnetic resonance imaging. RESULTS: Higher maternal urinary pregnancy-average or trimester-specific dialkyl, dimethyl, or diethyl phosphate concentrations were not associated with childhood BMI and the risk of overweight. In addition, we did not observe any association of dialkyl, dimethyl, or diethyl phosphate concentrations with total and regional body fat, abdominal visceral fat, liver fat, or pericardial fat at child age of 10 y. CONCLUSION: We observed no associations of maternal urinary dialkyl concentrations during pregnancy with childhood adiposity measures at 10 years of age. Whether these associations develop at older ages should be further studied.</p

Preconception and Early-Pregnancy Body Mass Index in Women and Men, Time to Pregnancy, and Risk of Miscarriage

Importance: Obesity in women is associated with reduced fertility and an increased risk of miscarriage. These associations might also be present across the full range of body mass index (BMI) categories as well as among men. Objective: To investigate the associations of preconception BMI in both partners with time to pregnancy and miscarriage. Design, Setting, and Participants: This population-based prospective cohort study was conducted in Rotterdam, the Netherlands, between August 9, 2017, and July 1, 2021. A total of 3604 women and their partners were included from the preconception period onward with follow-up until birth. The date of analysis was July 12, 2024. Exposure: Body mass index (calculated as weight in kilograms divided by height in meters squared) measured in preconception or early pregnancy. Main Outcome and Measures: Fecundability, defined as the probability of conceiving within 1 month; subfertility, defined as time to pregnancy or duration of actively pursuing pregnancy of more than 12 months or use of assisted reproductive technology; and miscarriage, defined as pregnancy loss before 22 weeks of gestation. These measures were assessed using questionnaires and via the obstetric caregiver. Results: The study population for time-to-pregnancy analyses consisted of 3033 episodes among women (median age, 31.6 years [IQR, 29.2-34.5 years]; median BMI, 23.5 [IQR, 21.2-26.5]) and 2288 episodes among men (median age, 33.4 years [IQR, 30.5-36.8 years]; median BMI, 24.9 [IQR, 23.0-27.4]). The study population for miscarriage analyses consisted of 2770 pregnancy episodes among women (median age, 31.5 years [IQR, 28.9-34.3 years]; median BMI, 23.5 [IQR, 21.3-26.7]) and 2189 pregnancy episodes among men (median age, 33.5 years [IQR, 30.4-36.8 years]; median BMI, 25.0 [IQR, 23.0-27.5]). Higher BMI in women and men was associated with lower fecundability: for every unit increase in BMI, fecundability decreased (fecundability ratio [FR]: women, 0.98 [95% CI, 0.97-0.99]; men, 0.99 [95% CI, 0.98-1.00]). Women with overweight (FR, 0.88 [95% CI, 0.80-0.98]) and obesity (FR, 0.72 [95% CI, 0.63-0.82]) had lower fecundability compared with women with normal weight. Compared with normal weight in women, underweight (odds ratio [OR], 1.88 [95% CI, 1.22-2.88]), overweight (OR, 1.35 [95% CI, 1.11-1.63]), and obesity (OR, 1.67 [95% CI, 1.30-2.13]) were associated with increased odds of subfertility. In men, obesity was associated with increased odds of subfertility (OR, 1.69 [95% CI, 1.24-2.31]). Compared with normal weight in women, overweight (OR, 1.49 [95% CI, 1.12-1.98]) and obesity (OR, 1.44 [95% CI, 1.00-2.08]) were associated with increased odds of miscarriage. Conclusions and Relevance: In this cohort study, BMI outside of the normal category in women and men during the preconception or early-pregnancy periods was associated with time to pregnancy and miscarriage. Optimizing BMI in women and men from the preconception period onward might be an important strategy to improve fertility outcomes.</p

Maternal Phthalate and Bisphenol Urine Concentrations during Pregnancy and Early Markers of Arterial Health in Children

BACKGROUND: Fetal exposure to endocrine-disrupting chemicals such as phthalates and bisphenols might lead to fetal cardiovascular developmental adaptations and predispose individuals to cardiovascular disease in later life. OBJECTIVES: We examined the associations of maternal urinary bisphenol and phthalate concentrations in pregnancy with offspring carotid intima-media thickness and distensibility at the age of 10 y. METHODS: In a population-based, prospective cohort study of 935 mother–child pairs, we measured maternal urinary phthalate and bisphenol concentrations at each trimester. Later, we measured child carotid intima-media thickness and distensibility in the children at age 10 y using ultrasound. RESULTS: Maternal urinary average or trimester-specific phthalate concentrations were not associated with child carotid intima-media thickness at age 10 y. Higher maternal average concentrations of total bisphenol, especially bisphenol A, were associated with a lower carotid intima-media thickness [differences −0:15 standard deviation score and 95% confidence interval (CI): −0:24, −0:09 and −0:13 (95% CI: −0:22, −0:04) per interquartile range (IQR) increase in maternal urinary total bisphenol and bisphenol A concentration]. Trimester-specific analysis showed that higher maternal third-trimester total bisphenol and bisphenol A concentrations were associated with lower child carotid intima-media thickness [differences −0:13 (95% CI: −0:22, −0:04) and −0:13 (95% CI: −0:22, −0:05) per IQR increase in maternal urinary bisphenol concentration]. Maternal urinary bisphenol or phthalate concentrations were not associated with child carotid distensibility. DISCUSSION: In this large prospective cohort, higher maternal urinary bisphenols concentrations were associated with smaller childhood carotid intima-media thickness. Further studies are needed to replicate this association and to identify potential underlying mechanisms. https://doi.org/10.1289/EHP10293

Associations of childhood BMI, general and visceral fat mass with metabolite profiles at school-age

Background: Childhood obesity increases metabolic disease risk. Underlying mechanisms remain unknown. We examined associations of body mass index (BMI), total body fat mass, and visceral fat mass with serum metabolites at school-age, and explored whether identified metabolites improved the identification of children at risk of a metabolically unhealthy phenotype. Methods: We performed a cross-sectional analysis among 497 children with a mean age of 9.8 (95% range 9.1, 10.6) years, participating in a population-based cohort study. We measured BMI, total body fat mass using DXA, and visceral fat mass using MRI. Serum concentrations of amino-acids, non-esterified-fatty-acids, phospholipids, and carnitines were determined using LC–MS/MS. Children were categorized as metabolically healthy or metabolically unhealthy, according to BMI, blood pressure, lipids, glucose, and insulin levels. Results: Higher BMI and total body fat mass were associated with altered concentrations of branched-chain amino-acids, essential amino-acids, and free carnitines. Higher BMI was also associated with higher concentrations of aromatic amino-acids and alkyl-lysophosphatidylcholines (FDR-corrected p-values &lt; 0.05). The strongest associations were present for Lyso.PC.a.C14.0 and SM.a.C32.2 (FDR-corrected p-values &lt; 0.01). Higher visceral fat mass was only associated with higher concentrations of 6 individual metabolites, particularly Lyso.PC.a.C14.0, PC.aa.C32.1, and SM.a.C32.2. We selected 15 metabolites that improved the prediction of a metabolically unhealthy phenotype, compared to BMI only (AUC: BMI: 0.59 [95% CI 0.47,0.71], BMI + Metabolites: 0.91 [95% CI 0.85,0.97]). Conclusions: An adverse childhood body fat profile, characterized by higher BMI and total body fat mass, is associated with metabolic alterations, particularly in amino acids, phospholipids, and carnitines. Fewer associations were present for visceral fat mass. We identified a metabolite profile that improved the identification of impaired cardiometabolic health in children, compared to BMI only.</p

Associations of Early Pregnancy Metabolite Profiles with Gestational Blood Pressure Development

Blood pressure development plays a major role in both the etiology and prediction of gestational hypertensive disorders. Metabolomics might serve as a tool to identify underlying metabolic mechanisms in the etiology of hypertension in pregnancy and lead to the identification of novel metabolites useful for the prediction of gestational hypertensive disorders. In a population-based, prospective cohort study among 803 pregnant women, liquid chromatography&mdash;mass spectrometry was used to determine serum concentrations of amino-acids, non-esterified fatty acids, phospholipids and carnitines in early pregnancy. Blood pressure was measured in each trimester of pregnancy. Information on gestational hypertensive disorders was obtained from medical records. Higher individual metabolite concentrations of the diacyl-phosphatidylcholines and acyl-lysophosphatidylcholines group were associated with higher systolic blood pressure throughout pregnancy (Federal Discovery Rate (FDR)-adjusted p-values &lt; 0.05). Higher concentrations of one non-esterified fatty acid were associated with higher diastolic blood pressure throughout pregnancy (FDR-adjusted p-value &lt; 0.05). Using penalized regression, we identified 12 individual early-pregnancy amino-acids, non-esterified fatty acids, diacyl-phosphatidylcholines and acyl-carnitines and the glutamine/glutamic acid ratio, that were jointly associated with larger changes in systolic and diastolic blood pressure from first to third trimester. These metabolites did not improve the prediction of gestational hypertensive disorders in addition to clinical markers. In conclusion, altered early pregnancy serum metabolite profiles mainly characterized by changes in non-esterified fatty acids and phospholipids metabolites are associated with higher gestational blood pressure throughout pregnancy within the physiological ranges. These findings are important from an etiological perspective and, after further replication, might improve the early identification of women at increased risk of gestational hypertensive disorders

Associations of maternal urinary bisphenol and phthalate concentrations with offspring reproductive development

Fetal exposure to bisphenols and phthalates may influence development of the reproductive system. In a population-based, prospective cohort study of 1059 mother-child pairs, we examined the associations of maternal gestational urinary bisphenols and phthalates concentrations with offspring reproductive development from infancy until 13 years. We measured urinary bisphenol and phthalate concentrations in each trimester. We obtained information on cryptorchidism or hypospadias after birth from medical records. At 9.7 years, we measured testicular and ovarian volume by MRI. At 13.5 years, we measured child Tanner stages and menstruation through questionnaire. We performed linear or logistic regression models for boys and girls to assess the associations of maternal urinary average and trimester-specific bisphenols and phthalates with child reproductive outcomes. Next, to further explore potential synergistic or additive effects of exposures together, we performed mixed exposure models using a quantile g computation approach. Models were adjusted for maternal age, ethnicity, body-mass index, education, parity, energy intake, smoking and alcohol use, and child's gestational age at birth, birthweight and body-mass index. In boys, no associations of maternal gestational phthalate or bisphenol with offspring cryptorchidism and hypospadias were found. Higher maternal high-molecular-weight phthalate and total bisphenol, but not phthalic acid or low-molecular-weight phthalate, were associated with larger child testicular volume at 10 years. Higher maternal phthalic acid and total bisphenol were associated with earlier genital and pubic hair development at 13 years, respectively (p-values<0.05). In girls, we found no associations of maternal urinary bisphenol and phthalate with ovarian volume or menstrual age. Only higher maternal urinary high-molecular-weight phthalate was associated with earlier pubic hair development at 13 years (p-values <0.05). Higher mixture exposure was associated with earlier pubic hair development in both sexes. In conclusion, higher maternal gestational urinary bisphenol and phthalate concentrations were associated with alterations in offspring reproductive development, mainly in boys

Associations of Early Pregnancy Metabolite Profiles with Gestational Blood Pressure Development

Blood pressure development plays a major role in both the etiology and prediction of gestational hypertensive disorders. Metabolomics might serve as a tool to identify underlying metabolic mechanisms in the etiology of hypertension in pregnancy and lead to the identification of novel metabolites useful for the prediction of gestational hypertensive disorders. In a population-based, prospective cohort study among 803 pregnant women, liquid chromatography—mass spectrometry was used to determine serum concentrations of amino-acids, non-esterified fatty acids, phospholipids and carnitines in early pregnancy. Blood pressure was measured in each trimester of pregnancy. Information on gestational hypertensive disorders was obtained from medical records. Higher individual metabolite concentrations of the diacyl-phosphatidylcholines and acyl-lysophosphatidylcholines group were associated with higher systolic blood pressure throughout pregnancy (Federal Discovery Rate (FDR)-adjusted p-values < 0.05). Higher concentrations of one non-esterified fatty acid were associated with higher diastolic blood pressure throughout pregnancy (FDR-adjusted p-value < 0.05). Using penalized regression, we identified 12 individual early-pregnancy amino-acids, non-esterified fatty acids, diacyl-phosphatidylcholines and acyl-carnitines and the glutamine/glutamic acid ratio, that were jointly associated with larger changes in systolic and diastolic blood pressure from first to third trimester. These metabolites did not improve the prediction of gestational hypertensive disorders in addition to clinical markers. In conclusion, altered early pregnancy serum metabolite profiles mainly characterized by changes in non-esterified fatty acids and phospholipids metabolites are associated with higher gestational blood pressure throughout pregnancy within the physiological ranges. These findings are important from an etiological perspective and, after further replication, might improve the early identification of women at increased risk of gestational hypertensive disorders