Maternal Phthalate Research Articles

Assessment of maternal phthalate exposure in urine across three trimesters and at delivery (umbilical cord blood and placenta) and its influence on birth anthropometric measures

Phthalates, commonly used in plastic manufacturing, have been linked to adverse reproductive effects. Our research from the Saudi Early Autism and Environment Study (2019–2022), involving 672 participants, focused on the impacts of maternal phthalate exposure on birth anthropometric measures. We measured urinary phthalate metabolites in 390 maternal samples collected during each of the three trimesters of pregnancy and in cord serum and placental samples obtained at delivery. We employed various statistical methods to analyze our data. Intraclass correlation coefficients were used to assess the consistency of phthalate measurements, generalized estimating equations were used to explore temporal variations across the trimesters, and linear regression models, adjusted for significant confounders and Bonferroni correction, were used for each birth outcome. Exposure to six phthalates was consistently high across trimesters, with 82 %–100 % of samples containing significant levels of all metabolites, except for mono-benzyl phthalate. We found a 3.15 %–3.73 % reduction in birth weight (BWT), 1.39 %–1.69 % reduction in head circumference (HC), and 3.63 %–5.45 % reduction in placental weight (PWT) associated with a one-unit increase in certain urinary di(2-ethylhexyl) phthalate (DEHP) metabolites during the first trimester. In the second trimester, exposure to MEP, ∑7PAE, and ∑LMW correlated with a 3.15 %–4.5 % increase in the APGAR 5-min score and increases in PWT by 8.98 % for ∑7PAE and 9.09 % for ∑LMW. Our study also highlighted the maternal-to-fetal transfer of DEHP metabolites, indicating diverse impacts on birth outcomes and potential effects on developmental processes. Our study further confirmed the transfer of DEHP metabolites from mothers to fetuses, evidenced by variable rates in the placenta and cord serum, with an inverse relationship suggesting a passive transfer mechanism. Additionally, we observed distinct phthalate profiles across these matrices, adversely impacting birth outcomes. In serum, we noticed increases associated with DEHP metabolites, with birth gestational age rising by 1.01 % to 1.11 %, HC by 2.84 % to 3.67 %, and APGAR 5-min scores by 3.77 % to 3.87 %. Conversely, placental analysis revealed a different impact: BWT decreased by 3.54 % to 4.69 %, HC reductions ranged from 2.57 % to 4.69 %, and chest circumference decreased by 7.13 %. However, the cephalization index increased by 3.67 %–5.87 %. These results highlight the complex effects of phthalates on fetal development, indicating their potential influence on crucial developmental processes like sexual maturation and brain development.

Possible associations between prenatal exposure to environmental pollutants and neurodevelopmental outcome in children

This study aimed to evaluate associations between prenatal and childhood exposure to phthalates and prenatal exposure to polychlorinated biphenyls (PCBs) and the development of 4-year-old children. Urinary metabolites of five phthalates were measured in women upon delivery, as well as serum concentrations of four PCB congeners. Postnatal phthalate metabolites were measured from children's urine obtained at the time of developmental assessment. The primary outcome was cognitive function as evaluated by the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) administered at 4 years. Secondary outcomes were motor function and response to sensory stimuli as evaluated by the Developmental Coordination Disorder Questionnaire (DCDQ) and Short Sensory Profile (SSP) that the mothers filled out, respectively. The study included 57 mother-child pairs. Higher maternal phthalate metabolite concentrations were inversely associated with WPPSI-III scores among boys and not among girls. After using linear regression models and controlling for confounding variables, we found that higher levels of monobenzyl phthalate (MBzP) were the ones associated with lower WPPSI-III scores (p=0.004, 95 %CI [-14.18; −3.16]), lower DCDQ scores (p=0.007, 95 %CI [-6.08; −1.17] and lower SSP scores (p=0.004, 95 %CI [-7.47; −1.79]). No association was found between child urinary phthalate metabolite concentrations or maternal PCB blood concentrations and developmental function. These findings indicate that higher prenatal phthalate metabolite levels may be associated with deficits in neurologic development of young boys.

Endocrine disruption and male reproductive disorders: unanswered questions.

Maternal exposure to endocrine-disrupting chemicals (EDCs) in human pregnancy is widely considered as an important cause of adverse changes in male reproductive health due to impaired foetal androgen production/action. However, the epidemiological evidence supporting this view is equivocal, except for certain phthalates, notably diethyl hexyl phthalate (DEHP). Maternal phthalate exposure levels associated with adverse reproductive changes in epidemiological studies are several thousand-fold lower than those needed to suppress foetal androgen production in rats, and direct studies using human foetal testis tissue show no effect of high phthalate exposure on androgen production. This conundrum is unexplained and raises fundamental questions. Human DEHP exposure is predominantly via food with highest exposure associated with consumption of a Western style (unhealthy) diet. This diet is also associated with increased exposure to the most common EDCs, whether persistent (chlorinated or fluorinated chemicals) or non-persistent (phthalates, bisphenols) compounds, which are found at highest levels in fatty and processed foods. Consequently, epidemiological studies associating EDC exposure and male reproductive health disorders are confounded by potential dietary effects, and vice versa. A Western diet/lifestyle in young adulthood is also associated with low sperm counts. Disentangling EDC and dietary effects in epidemiological studies is challenging. In pregnancy, a Western diet, EDC exposure, and maternal living in proximity to industrial sites are all associated with impaired foetal growth/development due to placental dysfunction, which predisposes to congenital male reproductive disorders (cryptorchidism, hypospadias). While the latter are considered to reflect impaired foetal androgen production, effects resulting from foetal growth impairment (FGI) are likely indirect. As FGI has numerous life-long health consequences, and is affected by maternal lifestyle, research into the origins of male reproductive disorders should take more account of this. Additionally, potential effects on foetal growth/foetal testis from the increasing use of medications in pregnancy deserves more research attention.

Association between prenatal phthalate exposure and ano-genital indices among offsprings in an Israeli cohort

BackgroundIn-utero phthalate exposure was shown to be associated with shortened anogenital distance (AGD) in male newborns, but findings among female are inconsistent. While phthalate exposure among pregnant women in Israel is widespread, no study has examined the association with offspring AGD. The objective of the current study was to investigate the association between maternal phthalates urinary concentration and offspring AGD at time of delivery among a birth cohort in Israel. MethodsWe measured spot urinary concentration of monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), mono-2-ethyl-5-hydroxyhexylphthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) among women presenting to the delivery room at Shamir Medical Center in Israel. Birthweight, length and AGD were measured in all newborns using a standardized protocol. Each AGD measurement was adjusted to weight (ano-genital index). Confounders included socio-demographic characteristics, comorbidities and obstetrical history. Univariate and multivariate analyses assessed the associations between phthalates, confounders and AGD. ResultsOverall, 193 mother and infant were analyzed. All newborns were born at term and had normal Apgar scores. Mean maternal age was 32 ± 4.7 years old. Mean birth weight and pregnancy week were 3183 ± 498 g and 39 ± 1.3, respectively. Median (IQR) urinary phthalate concentration adjusted to creatinine (ug/g) were 3.96 (2.2–6.6), 1.22 (0.7–2), 10.84 (7–20.4), 6.36 (3.3–11.2) and 0.64 (0.4–1.1) for MBP, MBzP, MECPP, MEHHP and MEOHP, respectively. Univariate comparison showed a significant association between higher than median MBzP concentration, higher Ano-Fourchetal index (AFI: 4.4 vs. 4.1, p = 0.037) and Ano-clitoral index (ACI: 11.5 vs. 10.4, p = 0.032) in infants. Total urinary phthalates concentration ≥26.25 μg/g was significantly associated with smaller penile width index (3.5 vs. 3.7, p = 0.022), higher ACI (11.6 vs. 10.3, p = 0.013) and a trend towards significance for higher AFI (4.3 vs. 4.1, p = 0.055). Following multivariate linear regression only PWI remained significantly associated with total phthalate urinary concentration. ConclusionsMaternal urinary phthalates concentration at delivery were not associated with female AGD, but total urinary phthalate concentration were inversely associated with penile width.

Maternal phthalate exposure and BMI trajectory in children-an 18-year birth cohort follow-up study.

Obesity is a major health concern worldwide. Previous studies have suggested that phthalate plasticizers are obesogens. However, the relationship between early-life phthalate exposure and long-term obesity development remains unknown. We investigated the association between prenatal phthalate exposure and children's body mass index (BMI) patterns in an 18-year birth cohort follow-up study in Taiwan. Our analytical lab quantified seven phthalate metabolites in maternal urine during pregnancy using quantitative liquid chromatography-tandem mass spectrometry. In addition, we calculated BMI z scores for participated children at each follow-up, utilized trajectory analysis to describe children's BMI z-score patterns at 2-18 years of age, and adopted generalized estimating equations (GEE) and multivariate logistic regression models to assess the association between prenatal phthalate exposure and BMI z scores in children. A total of 208 mother-child pairs were included in the analysis. Maternal urinary diethyl phthalate (DEP) metabolites were associated with the increase of BMI z scores in children aged 2-18 years in the GEE model. Doubled maternal urinary ∑mDEHP (3 mono hexyl-metabolites of di-ethyl-hexyl phthalate (DEHP) increased the risk of children being in the stable-high BMI trajectory group until the age of eighteen. We observed that BMI trajectories of children remained stable after the age of 5 years. During each follow-up, a higher frequency of overweight or obese was observed in children, ranging from 15.9% to 35.6% for girls and 15.2-32.0% for boys, respectively. Prenatal phthalate exposure was associated with increasing BMI z scores in children. Prenatal DEHP exposure was associated with a stable-high BMI trajectory in children up to the age of 18 years.

Gender associations between phthalate exposure and biomarkers of oxidative stress: A prospective cohort study.

Previous epidemiologic research has shown that phthalate exposure in pregnant women is related to adverse birth outcomes in a sex-specific manner. However, the biological mechanism of phthalate exposure that causes these birth outcomes remains poorly defined. In this research, we investigated the association between phthalate exposure and placental oxidative stress in a large population-based cohort study, aiming to initially explore the relationship between phthalate exposure and gene expression in placental oxidative stress in a sex-specific manner. Quantitative PCR was performed to measure the expression of placental inflammatory mRNAs (HO-1, HIF1α, and GRP78) in 2469 placentae. The multiple linear regression models were used to investigate the associations between mRNA and urinary phthalate monoesters. Phthalate metabolites monomethyl phthalate (MMP) and mono-n-butyl phthalate (MBP) were positively correlated with higher HIF1α expression in placentae of male fetuses (p < .05). Mono-benzyl phthalate (MBzP) increased the expression of HO-1, HIF1α, and GRP78 in placentae of male fetuses, and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) up-regulated the expression of HIF1α and GRP78. Additionally, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively correlated with HO-1, HIF1α, and GRP78 in placentae of female fetuses. Maternal phthalate exposure was associated with oxidative stress variations in placental tissues. The associations were closer in the placentas of male fetuses than in that of female ones. The placenta oxidative stress is worth further investigation as a potential mediator of maternal exposure-induced disease risk in children.

Association of maternal phthalates exposure and metabolic gene polymorphisms with congenital heart diseases: a multicenter case-control study

BackgroundThe majority of congenital heart diseases (CHDs) are thought to result from the interactions of genetics and the environment factors. This study aimed to assess the association of maternal non-occupational phthalates exposure, metabolic gene polymorphisms and their interactions with risk of CHDs in offspring.MethodsA multicenter case-control study of 245 mothers with CHDs infants and 268 control mothers of health infant was conducted from six hospitals. Maternal urinary concentrations of eight phthalate metabolites were measured by ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Twenty single nucleotide polymorphisms (SNPs) in cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and 19 (CYP2C19), uridine diphosphate (UDP) glucuronosyl transferase family 1 member A7 (UGT1A7), family 2 member B7 (UGT2B7) and B15(UGT2B15) genes were genotyped. The multivariate logistic regressions were used to estimate the association between maternal phthalates exposure or gene polymorphisms and risk of CHDs. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene–gene and gene–phthalates exposure interactions.ResultsThere was no significant difference in phthalate metabolites concentrations between the cases and controls. No significant positive associations were observed between maternal exposure to phthalates and CHDs. The SNPs of UGT1A7 gene at rs4124874 (under three models, log-additive: aOR = 1.74, 95% CI:1.28–2.37; dominant: aOR = 1.86, 95% CI:1.25–2.78; recessive: aOR = 2.50, 95% CI: 1.26–4.94) and rs887829 (under the recessive model: aOR = 13.66, 95% CI: 1.54–121) were significantly associated with an increased risk of CHDs. Furthermore, the associations between rs4124874 (under log-additive and dominant models) of UGT1A7 were statistically significant after the false discovery rate correction. No significant gene-gene or gene-phthalate metabolites interactions were observed.ConclusionsThe polymorphisms of maternal UGT1A7 gene at rs4124874 and rs887829 were significantly associated with an increased risk of CHDs. More large-scale studies or prospective study designs are needed to confirm or refute our findings in the future.

Sex-specific associations between maternal phthalate exposure and neurodevelopmental outcomes in children at 2 years of age in the APrON cohort

BackgroundThere is inconsistent evidence regarding the sex-specific associations between prenatal phthalate exposure and children’s neurodevelopment. This could be due to differences in the phthalate exposures investigated and the neurodevelopmental domains assessed. ObjectiveTo evaluate the associations between prenatal phthalate exposure and sex-specific outcomes on measures of cognition, language, motor, executive function, and behaviour in children 2 years of age in the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort. MethodsWe evaluated the associations between prenatal phthalate exposure and sex-specific neurodevelopmental outcomes in children at 2 years of age using data from 448 mothers and their children (222 girls, 226 boys). Nine phthalate metabolites were measured in maternal urine collected in the second trimester of pregnancy. Children’s cognitive, language, and motor outcomes were assessed using the Bayley Scales of Infant Development – Third Edition (Bayley-III). Parents completed questionnaires on children’s executive function and behavior, the Behavior Rating Inventory of Executive Function- Preschool Version (BRIEF-P) and Child Behavior Checklist (CBCL), respectively. Sex-stratified robust multivariate regressions were performed. ResultsHigher maternal concentrations of ΣDEHP and its metabolites were associated with lower scores on the Bayley-III Cognitive (β’s from −11.8 to −0.07 95% CI’s from −21.3 to −0.01), Language (β’s from −11.7 to −0. 09, 95% CI’s from −22.3 to −0.02) and Motor (β’s from −10.9 to −0.07, 95% CI from −20.4 to -0.01) composites in boys. The patterns of association in girls were in the opposite direction on the Cognitive and Language composites; on the Motor composite they were in the same direction as boys, but of reduced strength. Higher concentrations of ΣDEHP and its metabolites were associated with higher scores (i.e., more difficulties) on all measures of executive function in girls: inhibitory self-control (B’s from 0.05 to 0.11, 95% CI s from −0.01 to 0.15), flexibility (B’s from 0.04 to 0.11, 95% CI s from 0.01 to 0.21) and emergent metacognition (B’s from −0.01 to 0.06, 95% CIs from −0.01 to 0.20). Similar patterns of attenuated associations were seen in boys. Higher concentrations of ΣDEHP and its metabolites were associated with more Externalizing Problems in girls and boys (B’s from 0.03 to 6.82, 95% CIs from −0.08 to 12.0). Two phthalates, MMP and MBP, had sex-specific adverse associations on measures of executive function and behaviour, respectively, while MEP was positively associated with boys’ cognitive, language, and motor performance. Limited associations were observed between mixtures of maternal phthalates and sex-specific neurodevelopmental outcomes. ConclusionsMaternal prenatal concentrations of DEHP phthalates were associated with sex specific difference on measures of cognition and language at 2 years of age, specifically, poorer outcomes in boys. Higher exposure to DEHP was associated with poorer motor, executive function, and behavioural outcomes in girls and boys but the strength of these associations differed by sex. Limited associations were noted between phthalate mixtures and child neurodevelopment.

Prenatal phthalate exposure and cord blood DNA methylation

Exposure to phthalates has been shown to impede the human endocrine system, resulting in deleterious effects on pregnant women and their children. Phthalates modify DNA methylation patterns in infant cord blood. We examined the association between prenatal phthalate exposure and DNA methylation patterns in cord blood in a Korean birth cohort. Phthalate levels were measured in 274 maternal urine samples obtained during late pregnancy and 102 neonatal urine samples obtained at birth, and DNA methylation levels were measured in cord blood samples. For each infant in the cohort, associations between CpG methylation and both maternal and neonate phthalate levels were analyzed using linear mixed models. The results were combined with those from a meta-analysis of the levels of phthalates in maternal and neonatal urine samples, which were also analyzed for MEOHP, MEHHP, MnBP, and DEHP. This meta-analysis revealed significant associations between the methylation levels of CpG sites near the CHN2 and CUL3 genes, which were also associated with MEOHP and MnBP in neonatal urine. When the data were stratified by the sex of the infant, MnBP concentration was found to be associated with one CpG site near the OR2A2 and MEGF11 genes in female infants. In contrast, the concentrations of the three maternal phthalates showed no significant association with CpG site methylation. Furthermore, the data identified distinct differentially methylated regions in maternal and neonatal urine samples following exposure to phthalates. The CpGs with methylation levels that were positively associated with phthalate levels (particularly MEOHP and MnBP) were found to be enriched genes and related pathways. These results indicate that prenatal phthalate exposure is significantly associated with DNA methylation at multiple CpG sites. These alterations in DNA methylation may serve as biomarkers of maternal exposure to phthalates in infants and are potential candidates for investigating the mechanisms by which phthalates impact maternal and neonatal health.

Maternal phthalate exposure and dietary habits during pregnancy: what do we need to look for?

Maternal phthalate exposure and dietary habits during pregnancy: what do we need to look for?

Maternal exposure to phthalates and total gestational weight gain in the LIFECODES birth cohort.

Excessive gestational weight gain contributes to adverse maternal and neonatal outcomes. Environmental exposures such as phthalates may lead to metabolic dysregulation, and studies suggest possible associations between maternal phthalate exposure and altered gestational weight gain. We assessed the association between nine maternal phthalate metabolites and measures of total gestational weight gain (pre-pregnancy to median 35.1 weeks of gestation) in a case-control study nested within LIFECODES (N=379), a prospective birth cohort from Boston, Massachusetts (2006-2008). Our primary outcome was total gestational weight gain z score, a measure independent of gestational age that can provide a less biased estimate of this association. Our secondary outcomes were total gestational weight gain, rate of gestational weight gain, and adequacy ratio. The results were stratified by pre-pregnancy body mass index category. We found that concentrations of mono-(3-carboxypropyl) phthalate (MCPP) and mono-n-butyl phthalate (MBP) were positively associated with total gestational weight gain z scores among participants with obesity: adjusted mean difference (95% Confidence Interval [CI]) =0.242 (0.030 - 0.455) and 0.105 (-0.002 - 0.212) corresponding to an excess weight gain of 1.81kg and 0.77kg at 35 weeks of gestation per interquartile range-increase in MCPP and MBP, respectively. Also, among participants with obesity, MBP demonstrated a potential non-linear relationship with gestational weight gain in cubic spline models. These findings suggest that phthalates may be related to higher gestational weight gain, specifically, among individuals with pre-pregnancy obesity. Future research should investigate whether pregnant people with obesity represent a subpopulation with sensitivity to phthalate exposures.

Maternal Exposure To Phthalate Drives Skin Changes Associated With Increased Susceptibility To House Dust Mite Induced Atopic Dermatitis In Offspring

Epidemiologic studies indicate a link between maternal phthalate exposure and the development of Atopic Dermatitis (AD). Higher Trans-Epidermal Water Loss (TEWL) indicating skin barrier dysfunction, and cutaneous inflammation are hallmarks of AD. However, there is a little mechanistic information regarding the connection between maternal phthalate exposure offspring AD development.

Maternal phthalate exposure during pregnancy and testis function of young adult sons

BackgroundPhthalate exposure during fetal life may disrupt testicular development. Congruent with this, studies have found shorter anogenital distance, reduced penile size and altered hormone levels in infant boys whose mothers were exposed to higher levels of some phthalates during pregnancy. Few studies have explored if such adverse effects persist in adulthood. Thus, we aimed to explore if there is an association between fetal phthalate exposure and markers of testicular function in young adult men. MethodsIn a longitudinal mother-child cohort from Copenhagen, Denmark, we examined 100 young men whose mothers during pregnancy had serum drawn and analyzed for 34 phthalate metabolites. Examinations of the young men took place at 18–20 years of age and included measurements of adult markers of testicular function (reproductive hormones, penile size, anogenital distance (AGD), testis volume, semen quality) and growth factors. Associations between maternal serum concentrations of phthalate metabolites and reproductive measures in the young men were tested using multiple linear regression. ResultsMost consistently, higher maternal phthalate exposure was associated with higher luteinizing hormone (LH) but unchanged testosterone in adult sons. Congruently, higher maternal exposure was associated with lower total and free testosterone/LH ratios in adult sons. For example, twice as high maternal MiNP was associated with a 7.9 % (95 % CI 1.6–13.8) lower free testosterone/LH ratio. There was no consistent pattern of associations between the different phthalate metabolites and other reproductive hormones, clinical outcomes, or semen quality. None of the tested associations was significant after multiplicity adjustment. ConclusionsIn this exploratory study, higher maternal exposure to some phthalates was associated with impaired testicular Leydig cell function evidenced by a lower total and free testosterone/LH ratio in adult sons. This unique 18–20-year follow-up study raises concern and suggests that exposure of pregnant women to phthalates may have long-term effects on adult reproductive health in male offspring.

Associations between maternal phthalate exposure and neonatal neurobehaviors: The Taiwan maternal and infant cohort study (TMICS)

Previous studies have shown associations between prenatal phthalate exposure and neurobehavioral changes in children. However, few studies have focused on neonatal neurobehavioral development. This study aimed to examine the associations between prenatal phthalate exposure and neonatal neurobehavioral development in the early days of life after birth.This cohort study included 283 mother-infant pairs who participated in the Taiwan Mother Infant Cohort Study during 2012–2015. Each mother was interviewed, and urine samples were collected during the third trimester of pregnancy (weeks 29–40). Eleven common phthalate metabolites in maternal urine were analyzed. The Chinese version of the Neonatal Neurobehavioral Examination was used to evaluate early infant neurobehavioral development within five days of birth. We performed multiple linear regressions to explore the associations between phthalate exposure and neonatal neurobehavioral development. Sex differences in the association between phthalate metabolites and neonatal neurobehaviors were noted. Among girls, tertiles of phthalate metabolite concentrations were associated with worse behavioral responses and tone and motor patterns in the high-molecular-weight phthalate (HMW) and low-molecular-weight phthalate (LMW) groups. Girls in the highest tertile of di-2-ethylhexyl phthalate (DEHP) and mono-isobutyl phthalate (MiBP) had a negative association with tone and motor patterns. Girls in the highest tertile of mono-n-butyl phthalate (MnBP) and MiBP showed a negative association with behavioral responses. In contrast, tertiles of phthalate metabolite exposure were associated with improved neurobehaviors in mono-methyl phthalate (MMP) among boys. The highest tertile of MMP was positively associated with behavioral responses, primitive reflexes, and tone and motor patterns. Our findings suggest that maternal phthalate exposure affects neonatal neurobehavioral development in a sex-specific manner. Despite the relatively small sample size, our findings add to the existing research linking maternal phthalate exposure to neonatal neurobehavioral development. Additional research is needed to determine the potential long-term effects of prenatal phthalate exposure on children.

Co-exposure to phenols and phthalates during pregnancy with the difference of body size in twins at one month old

Humans are simultaneously exposed to phenols and phthalates (PAEs). However, the mixture effect of phenols and PAEs on the body size of twins is lacking. From 2016 to 2018, we recruited 228 pregnant twins and collected up to three urine samples. A total of 8 PAE metabolites and 7 phenols were detected in urine by liquid chromatography-tandem mass spectrometry. Chemical individual and mixture effects were estimated. Multivariable linear regression results presented the percentage change in twins' growth differences at one month old with maternal PAE and phenol exposure. These chemicals were positively associated with weight differences during the entire trimester. Moreover, the quantile g-computed model showed that increased urinary concentrations of all chemicals by one quartile were associated with a 22.85% (95%CI: 11.21–35.72%), 22.60% (95%CI: 12.31–33.83%), and 24.05% (95%CI: 13.11–36.05%) larger weight difference within twins in each trimester, respectively. Increasing all PAE metabolites and phenols by one quantile across the entire trimester, weight differences increased by 26.61% (95% CI: 15.79%, 38.44%), and height differences increased by 15.84% (95%CI: 3.92%, 29.13%). Co-exposure to PAEs and phenols may primarily play a role in twins’ growth.

Fetal exposure to phthalates and bisphenols and DNA methylation at birth: the Generation R Study

BackgroundPhthalates and bisphenols are non-persistent endocrine disrupting chemicals that are ubiquitously present in our environment and may have long-lasting health effects following fetal exposure. A potential mechanism underlying these exposure–outcome relationships is differential DNA methylation. Our objective was to examine the associations of maternal phthalate and bisphenol concentrations during pregnancy with DNA methylation in cord blood using a chemical mixtures approach.MethodsThis study was embedded in a prospective birth cohort study in the Netherlands and included 306 participants. We measured urine phthalates and bisphenols concentrations in the first, second and third trimester. Cord blood DNA methylation in their children was processed using the Illumina Infinium HumanMethylation450 BeadChip using an epigenome-wide association approach. Using quantile g-computation, we examined the association of increasing all mixture components by one quartile with cord blood DNA methylation.ResultsWe did not find evidence for statistically significant associations of a maternal mixture of phthalates and bisphenols during any of the trimesters of pregnancy with DNA methylation in cord blood (all p values > 4.01 * 10–8). However, we identified one suggestive association (p value < 1.0 * 10–6) of the first trimester maternal mixture of phthalates and bisphenols and three suggestive associations of the second trimester maternal mixture of phthalates and bisphenols with DNA methylation in cord blood.ConclusionsAlthough we did not identify genome-wide significant results, we identified some suggestive associations of exposure to a maternal mixture of phthalates and bisphenols in the first and second trimester with DNA methylation in cord blood that need further exploration in larger study samples.

Mediation Effects of Placental Inflammatory Transcriptional Biomarkers on the Sex-Dependent Associations between Maternal Phthalate Exposure and Infant Allergic Rhinitis: A Population-Based Cohort Study

ObjectivePrenatal phthalate exposure has been associated with placental inflammatory factors and infant allergic rhinitis (AR). However, the results are inconclusive. We designed a population-based cohort study to examine the effects of placental inflammatory biomarkers on the sex-dependent associations between maternal phthalate exposure and infant AR. MethodsA total of 2,348 pregnant women from Ma'anshan, Anhui Province, China, who were screened before antenatal visits and met the inclusion criteria, were included in the present study. We assessed AR in their offspring aged 36 months with a questionnaire. Quantitative PCR was performed to measure placental inflammatory factor mRNAs. The independent samples t-test and multivariable logistic regression were used to determine the associations between infant AR and maternal phthalates. ResultsChildhood AR may be related to education and family monthly income (P = 0.01). The phthalate metabolites, mono (2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-hydroxyl) phthalate (MEHHP), in pregnant women were associated with a significantly increased risk for infant AR in males [P < 0.05; odds ratio (OR): 1.285; 95% confidence interval (CI): 1.037–1.591, and OR: 1.232, 95% CI: 1.008–1.507, respectively], but not females. Additionally, irritably-increased expression levels of HO-1 and IL-4 were associated with AR in male infants (OR: 1.175; 95% CI: 1.038–1.329 and OR: 1.181; 95% CI: 1.056–1.322, respectively). The association between maternal urinary MEHHP and placental HO-1 was marginally significant according to mediation analysis. ConclusionThe associations of maternal MEHHP and MEOHP levels with fetal AR in males were significant. Placental HO-1 was a fractional mediator in the associations between MEHHP and AR. Thus, the placenta should be further investigated as a potential mediator of maternal exposure-induced disease risk in children.

Maternal Serum and Placental Metabolomes in Association with Prenatal Phthalate Exposure and Neurodevelopmental Outcomes in the MARBLES Cohort.

Prenatal exposure to phthalates, a family of endocrine-disrupting plasticizers, is associated with disruption of maternal metabolism and impaired neurodevelopment. We investigated associations between prenatal phthalate exposure and alterations of both the maternal third trimester serum metabolome and the placental metabolome at birth, and associations of these with child neurodevelopmental outcomes using data and samples from the Markers of Autism Risk in Babies Learning Early Signs (MARBLES) cohort. The third trimester serum (n = 106) and placental (n = 132) metabolomes were investigated using 1H nuclear magnetic resonance spectroscopy. Children were assessed clinically for autism spectrum disorder (ASD) and cognitive development. Although none of the urinary phthalate metabolite concentrations were associated with maternal serum metabolites after adjustment for covariates, mixture analysis using quantile g-computation revealed alterations in placental metabolites with increasing concentrations of phthalate metabolites that included reduced concentrations of 2-hydoxybutyrate, carnitine, O-acetylcarnitine, glucitol, and N-acetylneuraminate. Child neurodevelopmental outcome was not associated with the third trimester serum metabolome, but it was correlated with the placental metabolome in male children only. Maternal phthalate exposure during pregnancy is associated with differences in the placental metabolome at delivery, and the placental metabolome is associated with neurodevelopmental outcomes in males in a cohort with high familial ASD risk.

Di-2-ethylhexyl phthalate affects zinc metabolism and neurogenesis in the developing rat brain

We previously observed that developmental marginal zinc deficiency affects neurogenesis. Maternal phthalate exposure could disrupt fetal zinc homeostasis by triggering an acute phase response, causing maternal liver zinc retention that limits zinc availability to the fetus. Thus, we currently investigated whether exposure to di-2-ethylhexyl phthalate (DEHP) during gestation in rats alters fetal brain neurogenesis by impairing zinc homeostasis. Dams consumed an adequate (25 μg zinc/g diet) (C) or a marginal zinc deficient (MZD) (10 μg zinc/g diet) diet, without or with DEHP (300 mg/kg BW) (C + DEHP, MZD + DEHP) from embryonic day (E) 0 to E19. To evaluate neurogenesis we measured parameters of neural progenitor cells (NPC) proliferation and differentiation. Maternal exposure to DEHP and/or zinc deficiency lowered fetal brain cortical tissue (CT) zinc concentrations. Transcription factors involved in NPC proliferation (PAX6, SOX2, EMX1), differentiation (TBR2, TBR1) and mature neurons (NeuN) were lower in MZD, MZD + DEHP and C + DEHP than in C E19 brain CT, being the lowest in the MZD + DEHP group. VGLUT1 levels, a marker of glutamatergic neurons, showed a similar pattern. Levels of a marker of GABAergic neurons, GAD65, did not vary among groups. Phosphorylated ERK1/2 levels were reduced by both MZD and DEHP, and particularly in the MZD + DEHP group. MEHP-treated human neuroblastoma IMR-32 cells and E19 brains from DEHP-treated dams showed that the zinc-regulated phosphatase PP2A can be in part responsible for DEHP-mediated ERK1/2 downregulation and impaired neurogenesis. Overall, gestational exposure to DEHP caused secondary zinc deficiency and impaired neurogenesis. These harmful effects could have long-term consequences on the adult offspring brain structure and function.

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 standard deviation score and 95% confidence interval (CI): , and (95% CI: , ) 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 (95% CI: , ) and (95% CI: , ) 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