Maternal Urinary Metabolites Research Articles

A green and sensitive electromembrane extraction (EME) method for the determination of dialkylphosphates in maternal urine and amniotic fluid

Organophosphates compounds are extensively used pesticides, whose metabolites, dialkyl phosphates, are considered as bioindicators of human exposure. Recently, research has indicated that they can affect thyroid endocrine function. Pregnant women are a particularly vulnerable cohort to these effects due to concerns about prenatal exposure to environmental pollutants. For the first time an electromembrane microextraction method is proposed for the simultaneous determination of seven dialkylphosphate metabolites in maternal urine and amniotic fluid, which is compatible with mass spectrometry detection and achieves highly sensitive levels of quantitation. Dialkylphosphates were extracted from a 10 mL donor solution at pH 7 into a 50 µL acceptor solution at pH 12 using 1-octanol as the supported liquid membrane and applying 60 V for 10 min at 600 rpm. The obtained extracts were analysed by ion pair liquid chromatography coupled to a triple quadrupole mass spectrometer, using an Acquity UPLC® BEH C18 column (100 mm × 2.1 mm i.d., 1.7 µm particle size) at 30 °C. Under optimal extraction conditions, the preconcentration factors were achieved were up to 178-fold, allowing for high sensitivity levels, in the order of ng mL−1. The limits of quantitation were within 0.075 ng mL−1 (diethyl thiophosphate) and 1.67 ng mL−1 (dimethyl phosphate) in maternal urine samples and within 0.015 ng mL−1 (diethyl thiophosphate) and 0.5 ng mL−1 (dimethyl dithiophosphate) in amniotic fluid samples. The comparative study revealed a significant improvement in terms of analysis time, sensitivity, greenness, and practicality. Finally, the applicability of the method for the determination of selected dialkylphosphates was demonstrated in paired maternal urine and amniotic fluid samples. These results suggest potential placental transfer to the offspring.

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.

Maternal exposure to polycyclic aromatic hydrocarbons during pregnancy and timing of pubertal onset in a longitudinal mother–child cohort in rural Bangladesh

BackgroundIn experimental studies, several polycyclic aromatic hydrocarbons (PAHs) have shown endocrine disrupting properties, but very few epidemiological studies have examined their impact on pubertal development and results have been heterogenous. ObjectiveTo explore if maternal PAH exposure during pregnancy was associated with the offspring’s timing of pubertal onset. MethodsWe studied 582 mother-daughter dyads originating from a population-based cohort in a rural setting in Bangladesh. Maternal urinary samples, collected in early pregnancy (on average, gestational week 8), were analyzed for monohydroxylated metabolites of phenanthrene (1-OH-Phe, Σ2-,3-OH-Phe, and 4-OH-Phe), fluorene (Σ2-,3-OH-Flu), and pyrene (1-OH-Pyr) using liquid chromatography with tandem mass spectrometry (LC-MS/MS). The girls were interviewed on two separate occasions concerning date of menarche, as well as breast and pubic hair development according to Tanner. Associations were assessed using Kaplan-Meier analysis and multivariable-adjusted Cox proportional hazards regression or ordered logistic regression. ResultsIn early pregnancy, the mothers’ median urinary concentrations of Σ1-,2-,3-,4-OH-Phe, Σ2-,3-OH-Flu, and 1-OH-Pyr were 3.25 ng/mL, 2.0 ng/mL, and 2.3 ng/mL respectively. At the second follow-up, 78 % of the girls had reached menarche, and the median age of menarche was 12.7 ± 0.81 years. Girls whose mothers belonged to the second and third quintiles of ΣOH-Phe metabolites had a higher rate of menarche, indicating a younger menarcheal age (HR 1.39; 95 % CI 1.04, 1.86, and HR 1.41; 95 % CI 1.05, 1.88, respectively), than girls of mothers in the lowest quintile. This trend was not observed in relation to either breast or pubic hair development. None of the other maternal urinary PAH metabolites or the sum of all thereof in early pregnancy were associated with age at menarche or pubertal stage. ConclusionsIndications of non-monotonic associations of prenatal phenanthrene exposure with the daughters’ age of menarche were found, warranting further investigation.

Prenatal arsenic metabolite exposure is associated with increased newborn mitochondrial DNA copy number: evidence from a birth cohort study.

While mitochondria are susceptible to environmental detriments, little is known about potential associations between arsenic metabolites and mitochondria DNA copy number (mtDNAcn). We attempted to examine whether maternal urinary arsenic metabolite levels in different trimesters were related to neonatal cord blood mtDNAcn. We included 819 mother-newborn pairs embedded in an in-progress birth cohort survey performed from April 2014 to October 2016 in Wuhan, China. We determined maternal urinary arsenic species concentrations in different trimesters. We determined cord blood mtDNAcn using quantitative real-time polymerase chain reaction. In covariate-adjusted models, each one-unit increment of dimethylated arsenic (DMA) and total arsenic (TAs) in the third trimester was related to 8.43% (95% CI 1.13%, 16.26%) and 12.15% (95% CI 4.35%, 20.53%) increases in mtDNAcn, respectively. The dose-response trend with statistical significance was observed across tertiles of DMA and TAs in the third trimester with mtDNAcn (DMA percent changes (%Δ) = 25.60 (95% CI 6.73, 47.82), for the highest vs the lowest tertile (P = 0.02); TAs %Δ = 40.31 (95% CI 19.25, 65.10), for the highest vs the lowest tertile (P = 0.0002)). These findings may prove the relationships between prenatalarsenic species levelsand neonatalmitochondrial dysfunction.

Placental transcriptome variation associated with season, location, and urinary prenatal pyrethroid metabolites of Thai farm-working women

Prenatal exposure to pyrethroids is linked to adverse health effects in early life and proper placental function is critical to fetal development. This study explores the impact of prenatal pyrethroid exposure, as well as factors impacting exposure and effect, on the placental transcriptome, to understand pyrethroid exposures' relationship to placental function. The study of Asian Women and their Offspring's Development and Environmental Exposures (SAWASDEE) recruited pregnant farm-working women from two agricultural districts in the Chiang Mai province of Thailand between 2017 and 2019. This cohort was predominantly exposed to cypermethrin (type II), alongside pyrethroids such as cyfluthrin (type II) and permethrin (type I). In 253 participants, maternal urinary pyrethroid metabolites, 3-phenoxybenzoic acid (PBA), cis-3-(2,2-Dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (CDCCA), and trans-3-(2,2-Dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (TDCCA) were measured in early, middle, and late pregnancy and adjusted for urinary creatinine. The placental transcriptome was analyzed using RNA-Seq. Using generalized linear regression, we identified differentially expressed genes (DEGs) associated with the sum of each metabolite across pregnancy, as well as those associated with location of residence and season of birth. Pathway and upstream transcription factor analyses were performed to examine potential mechanisms associated with DEGs. Notably, TDCCA and CDCCA levels peaked in late pregnancy, with significant regional differences, particularly higher levels in the Fang region. Placental gene expression analysis showed no DEGs associated with individual metabolites at FDR<0.05. However, 251 DEGs by location, implicating immune response and oxidative phosphorylation pathways, were identified, while season of birth was associated with 2585 DEGs, over-represented in fibrosis signaling and metabolism pathways. Finally, transcription factor analysis identified 226 and 282 transcription factors associated with location and season, respectively, related to cell proliferation, differentiation, and the immune system. These alterations may have significant implications for fetal development and other pathologic processes, highlighting the importance of monitoring environmental exposures during pregnancy.

Electro-assisted liquid phase microextraction for the determination of parabens and their main metabolites in maternal urine and amniotic fluid samples

In this study, an electro assisted liquid phase microextraction (EA-LPME) procedure to determine seven parabens (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and benzyl paraben) and three of their key hydroxy metabolites (4-hydroxy, 3,4-dihydroxy, and 3,4,5-trihydroxy benzoic acid) was optimised in maternal urine and amniotic fluid obtained at delivery from pregnant women. The samples were analysed by ultra-high-performance liquid chromatography coupled with electrospray ionisation tandem mass spectrometry (UPLC-ESI-MS/MS). PHBs and their metabolites were extracted from a pH 4 donor solution (10 mL) into a pH 13 acceptor solution (50 µL) using 1-octanol as the supported liquid membrane (SLM) and 30 V for 40 min at 400 rpm. Under optimal operational conditions, enrichment factors between 10 and 90 were achieved, and low quantitation limits within 0.022–0.20ng mL−1 and 0.025–0.18 ng mL−1, were obtained for amniotic fluid and urine, respectively. The proposed analytical procedure was satisfactorily applied for the determination of target compounds in seven paired maternal urine and amniotic fluid samples to evaluate the possible placental transfer of these compounds from mothers to babies.

Maternal and newborn metabolomic changes associated with urinary polycyclic aromatic hydrocarbon metabolite concentrations at delivery: an untargeted approach.

Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with adverse human health outcomes. To explore the plausible associations between maternal PAH exposure and maternal/newborn metabolomic outcomes, we conducted a cross-sectional study among 75 pregnant people from Cincinnati, Ohio. We quantified 8 monohydroxylated PAH metabolites in maternal urine samples collected at delivery. We then used an untargeted high-resolution mass spectrometry approach to examine alterations in the maternal (n = 72) and newborn (n = 63) serum metabolome associated with PAH metabolites. Associations between individual maternal urinary PAH metabolites and maternal/newborn metabolome were assessed using linear regression adjusted for maternal and newborn factors while accounting for multiple testing with the Benjamini-Hochberg method. We then conducted functional analysis to identify potential biological pathways. Our results from the metabolome-wide associations (MWAS) indicated that an average of 1% newborn metabolome features and 2% maternal metabolome features were associated with maternal urinary PAH metabolites. Individual PAH metabolite concentrations in maternal urine were associated with maternal/newborn metabolome related to metabolism of vitamins, amino acids, fatty acids, lipids, carbohydrates, nucleotides, energy, xenobiotics, glycan, and organic compounds. In this cross-sectional study, we identified associations between urinary PAH concentrations during late pregnancy and metabolic features associated with several metabolic pathways among pregnant women and newborns. Further studies are needed to explore the mediating role of the metabolome in the relationship between PAHs and adverse pregnancy outcomes.

Di(2-ethylhexyl) phthalate mediates IL-33 production via aryl hydrocarbon receptor and is associated with childhood allergy development.

Few studies assess cord blood biomarkers to predict prenatal exposure to di(2-ethylhexyl) phthalate (DEHP) on the development of allergic diseases later in childhood. IL-33 has been indicated to play an important role in allergic diseases. We evaluated the association of prenatal DEHP exposure and IL-33 in cord blood on the development of allergic diseases. We also investigated the mechanism of DEHP in human lung epithelial cells and asthma animal models. 66 pregnant women were recruited, and their children followed when they were aged 3 years. Maternal urinary DEHP metabolites were determined using liquid chromatography-electrospray-ionization-tandem mass spectrometry. The effect of DEHP on IL-33 production was investigated in human lung epithelial cells and club cell-specific aryl hydrocarbon receptor (AhR) deficiency mice. ELISA and RT-PCR, respectively, measured the IL-33 cytokine concentration and mRNA expression. The concentrations of maternal urinary DEHP metabolites and serum IL-33 in cord blood with childhood allergy were significantly higher than those in the non-childhood allergy group. DEHP and MEHP could induce IL-33 production and reverse by AhR antagonist and flavonoids in vitro. Enhanced ovalbumin-induced IL-4 and IL-33 production in bronchoalveolar lavage fluid (BALF) by DEHP exposure and suppressed in club cell-specific AhR null mice. Kaempferol has significantly reversed the DEHP effect in the asthma animal model. Cord blood IL-33 level was correlated to childhood allergy and associated with maternal DEHP exposure. IL-33 might be a potential target to assess the development of DEHP-related childhood allergic disease. Flavonoids might be the natural antidotes for DEHP.

Prenatal exposures to isoflavones and neurobehavioral development in children at 2 and 4 years of age: A birth cohort study

Isoflavones (ISOs) are plant-derived estrogen-like compounds, which were already proved with cognition benefits on elderly people. However, studies assessing the associations between prenatal ISOs exposure and children’s neurodevelopment are scarce. This study aimed to examine the associations between maternal urinary ISOs concentrations, including genistein (GEN), daidzein (DAD), glycitein (GLY), and metabolite equol (EQU), and children’s neurodevelopment, based on a Chinese cohort study. Participants in this study were pregnant women recruited at 12–16 weeks of gestation, and they provided a single spot urine sample for the ISOs assay. Neurodevelopment was measured using the Child Behavior Checklist (CBCL) at 2 and 4 years of age. Negative binomial regression analysis and Generalized Estimating Equation (GEE) were performed to examine the associations between maternal urinary ISOs concentrations and CBCL scores. Associations were observed between moderate levels of prenatal ISOs exposure and decreased risks of childhood neurobehavioral problems, while the highest level of prenatal ISOs exposure was associated with increased risks of neurobehavioral problems among children. The neuroprotective effects were consistently between moderate DAD exposure and specific neurobehavioral problems, across different ages and sexes. For example, compared with the lowest exposure level, the third quartile group was associated with less Anxious/Depressed problems in boys at 2 years of age (RR=0.72 (95%CI: 0.52, 0.99)), girls at 2 years of age (RR=0.70 (95%CI: 0.46, 1.06)), boys at 4 years of age (RR=0.73 (95%CI: 0.55, 0.96)), and girls at 4 years of age (RR=0.95 (95%CI: 0.68, 1.31)).

Associations between prenatal exposure to polycyclic aromatic hydrocarbons and thyroid hormones in umbilical cord blood.

We explored the association between maternal urinary polycyclic aromatic hydrocarbon (PAH) metabolites and thyroid hormones in umbilical cord blood in 120 pairs of pregnant women and newborns. Maternal urinary PAH metabolites were measured using high-performance liquid chromatography with tandem mass spectrometry. Thyroid hormones were measured using a flow fluorescence assay. The dose-response relationship between PAH metabolites and thyroid hormones was analyzed using the generalized linear model and restricted cubic spline model. Results showed that ƩOH PAHs in maternal urine had a negative effect on triiodothyronine (T3). Associations between maternal urinary PAH metabolites and thyroid hormones in umbilical cord blood plasma were observed. Prenatal exposure to PAHs could affect neonatal thyroid hormones, thereby disrupting neonatal thyroid function.

Maternal environmental, occupational, and urinary metabolite levels of benzene compounds and their association with congenital heart diseases in offspring: a case‒control study in China

The conclusions about the association of maternal pregnancy environment, occupation, and benzene compounds with fetal CHD are not entirely consistent. Eight hundred seven CHD cases and 1008 controls were included in this study. All occupations were classified and coded against the Occupational Classification Dictionary of the People’s Republic of China (2015 version). Logistic regressions were used to explore the correlation among environmental factors, occupation types, and CHDs in offspring. We found that living near public facilities and having exposure to chemical reagents and hazardous substances were significant risk factors for CHDs in offspring. We found that offspring of mothers who worked in agriculture and similar work during pregnancy suffered from CHD. The risk of all CHDs in the offspring of pregnant women working in production manufacturing and related work was significantly higher than that in unemployed pregnant women, the risk was also observed in 4 subtypes of CHDs. We compared the concentrations of the five metabolite (MA, mHA, HA, PGA, and SPMA) levels of benzene compounds in the urine of mothers in case and control groups and found no significant differences. Our study suggests that maternal exposure during pregnancy and certain environmental and occupational conditions are risk factors for CHD in offspring, but did not support an association between concentrations of metabolites of benzene compounds in the urine of pregnant women and CHDs in their offspring.

Polycyclic aromatic hydrocarbon (PAH) exposure during pregnancy and child anthropometry from birth to 10 years of age: Sex-specific evidence from a cohort study in rural Bangladesh

Polycyclic aromatic hydrocarbons (PAHs) have endocrine disrupting properties and they cross the placental barrier, but studies on gestational exposure and child anthropometry are inconclusive. We aimed to elucidate the impact of early gestational PAH exposure on anthropometry from birth to 10 years of age in 1295 mother-child pairs from a nested sub-cohort of the MINIMat trial in Bangladesh. Several PAH metabolites [1-hydroxyphenanthrene (1-OH-Phe), Σ2-,3-hydroxyphenanthrene (Σ2-,3-OH-Phe), 4-hydroxyphenanthrene (4-OH-Phe), 1-hydroxypyrene (1-OH-Pyr), Σ2-,3-hydroxyfluorene (Σ2-,3-OH-Flu)] were quantified in spot urine collected around gestational week 8 using LC-MS/MS. Child weight and height were measured at 19 occasions from birth to 10 years. Multivariable-adjusted regression models were used to assess associations of maternal PAH metabolites (log2-transformed) with child anthropometry. The median concentration of 1-OH-Phe, Σ2-,3-OH-Phe, 4-OH-Phe, 1-OH-Pyr and Σ2-,3-OH-Flu was 1.5, 1.9, 0.14, 2.5, and 2.0 ng/mL, respectively. All maternal urinary PAH metabolites were positively associated with newborn weight and length and all associations were more pronounced in boys than in girls (p interaction for all <0.14). In boys, the strongest associations were observed with Σ2-,3-OH-Phe and Σ2-,3-OH-Flu for which each doubling increased mean birth weight by 41 g (95% CI: 13; 69 and 12; 70) and length by 0.23 cm (0.075; 0.39) and 0.21 cm (0.045; 0.37), respectively. Maternal urinary PAH metabolites were not associated with child anthropometry at 10 years. In longitudinal analysis, however, maternal urinary PAH metabolites were positively associated with boys' weight-for-age (WAZ) and height-for-age Z-scores (HAZ) from birth to 10 years, but only the association of 4-OH-Phe with HAZ was significant (B: 0.080 Z-scores; 95% CI 0.013, 0.15). No associations were observed with girls’ WAZ or HAZ. In conclusion, gestational PAH exposure was positively associated with fetal and early childhood growth, especially in boys. Further studies are needed to confirm causality and to explore long-term health effects.

Gestational exposure to organophosphate esters and infant anthropometric measures in the first 4 weeks after birth.

Few studies have examined whether gestational exposure to organophosphate esters (OPEs), widely used chemicals with potential endocrine-disrupting potency and developmental toxicity, is associated with impaired infant growth. We analyzed data from 329 mother-infant pairs in the Health Outcomes and Measures of the Environment (HOME) Study (2003-2006, Cincinnati, Ohio, USA). We quantified concentrations of four OPE metabolites in maternal urine collected at 16 and 26 weeks of gestation, and at delivery. We calculated z-scores using 2006 World Health Organization (WHO) child growth standards for the 4-week anthropometric measures (weight, length, and head circumference), the ponderal index, and weekly growth rates. We used multiple informant models to examine window-specific associations between individual OPE metabolites and anthropometric outcomes. We further modeled OPEs as a mixture for window-specific associations with 4-week anthropometric outcomes using mean field variational Bayesian inference procedure for lagged kernel machine regression (MFVB-LKMR). We stratified the models by infant sex. Diphenyl phosphate (DPHP) in mothers at 16 weeks, and bis(2-chloroethyl) phosphate (BCEP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) at delivery were positively associated with z-scores of weight, length, and head circumference in all infants at 4 weeks of age. After stratifying by infant sex, positive associations were only observed in males for DPHP at 16 weeks and BCEP at delivery and in females for BDCIPP at delivery. Negative associations not present in all infants were observed in males for di-n-butyl phosphate (DNBP) at 26 weeks of gestation with weight z-score and DPHP at delivery with head circumference z-score. Results were generally similar using MFVB-LKMR models with more conservative 95 % credible intervals. We did not identify consistent associations of gestational OPE metabolite concentrations with the ponderal index and weekly growth rates. In this cohort, exposure to OPEs during gestation was associated with altered infant anthropometry at 4 weeks after birth.

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.

Exposure assessment of acetaminophen use in pregnancy: a study comparing self-reported intake with maternal and newborn biomarker measures

Background: Acetaminophen (APAP) is the most commonly used medication during pregnancy. Increasingly, studies have reported potential adverse associations between maternal prenatal use of APAP and offspring asthma, adverse reproductive outcomes, and neurodevelopmental disorders. However, most studies have relied on self-reported maternal exposure which has the potential for exposure misclassifications. We conducted this study to compare maternal self-reported APAP intake and three acetaminophen metabolites measured in urine collected during pregnancy and umbilical cord serum samples. Methods We used maternal interview data and biospecimens from the Nutrition in Pregnancy cohort of 2291 pregnant women recruited from Connecticut and Western Massachusetts during 1996-2000. We selected three exposure groups including 10 mothers who reported frequent intake (14 days+) of APAP in the first 3 months of pregnancy, 10 who reported frequent intake in the last 3 months of pregnancy, and 10 who reported never using APAP in these two periods from the cohort. We analyzed three APAP metabolites (parent compound, acetaminophen glucuronide, and 3-(N-acetyl-l-cystein-S-yl)-acetaminophen) levels in the maternal urine (avg. 24 gestational weeks) and the umbilical cord serum samples. Results The parent APAP compound and 3-(N-acetyl-l-cystein-S-yl)-acetaminophen) were detected in all urine and serum samples analyzed (100%), while acetaminophen glucuronide was less detectable in the cord serum (40% vs. 100% in urine). APAP metabolites in maternal urine and cord serum were correlated (r=0.43-0.70) within mother-child pairs. All three urinary and cord serum APAP metabolite levels were more strongly correlated with the reported number of days of APAP intake in late pregnancy (r=0.57-0.73; p-values &amp;#x3c;0.03, rank tests), and less with early pregnancy intake (r=0.18-0.34; p-values 0.21-0.60, rank tests). Conclusions Our findings suggest detailed intake data collected in maternal interviews is an efficient and valid measure to indicate exposure to APAP in pregnancy, while biomarker measures can be used to represent a specific exposure period of interest.

Maternal urinary organophosphate ester metabolite concentrations and glucose tolerance during pregnancy: The HOME Study.

Endocrine-disrupting chemicals may alter glucose homeostasis, especially during pregnancy. Biomonitoring studies suggest ubiquitous human exposure to organophosphate esters (OPEs), chemicals with endocrine-disrupting capabilities. Few studies have examined the association between maternal exposure to OPEs and blood glucose during pregnancy. With data from 301 pregnant women in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort in Cincinnati, Ohio, USA, we examined whether OPE concentrations were associated with changes in blood glucose. We quantified four OPE metabolites in maternal spot urine samples collected at 16- and 26-weeks pregnancy. We extracted results from the glucose challenge test (GCT) and oral glucose tolerance test (OGTT) via medical chart review. Women with GCT ≥ 140mg/dL or any abnormal values in OGTT (≥ 95mg/dL fasting glucose, ≥ 180mg/dL 1-h glucose, ≥ 155mg/dL 2-h glucose, ≥ 140mg/dL 3-h glucose) were defined as having elevated glucose levels. We used linear regression and Bayesian Kernel Machine Regression (BKMR) to estimate the associations of individual OPE metabolites and OPE mixtures with blood glucose levels during pregnancy. We used modified Poisson regression to estimate the associations of OPE metabolite concentrations with elevated glucose levels. We further examined effect measure modification by maternal characteristics (age, pre-pregnancy body mass index [BMI], and race/ethnicity). Diphenyl phosphate (DPHP) had the highest geometric mean concentration of the urinary OPE metabolites (1.83μg/L at 16 weeks, 1.24μg/L at 26 weeks). Thirty women (10.0%) had elevated glucose levels. Individual OPE metabolites or their mixtures were not significantly associated with continuous GCT results. We did not observe effect measure modification by maternal age, pre-pregnancy BMI categories, or race/ethnicity. Compared with women in the 1st tertile of average DPHP of 16- and 26 weeks of pregnancy, women in the 3rd tertile tended to have a reduced risk of elevated glucose levels (RR=0.41, 95% CI=0.16-1.06, p for trend=0.06). In this cohort, maternal urinary OPE metabolite concentrations were weakly associated with blood glucose levels during pregnancy.

Maternal exposure to DDT, DDE, and pyrethroid insecticides for malaria vector control and hypospadias in the VHEMBE birth cohort study, Limpopo, South Africa

Hypospadias is the ectopic opening of the urethra on the penis or scrotum. Exposure to estrogenic and/or anti-androgenic chemicals in utero may play an etiologic role. DDT and the pyrethroids cypermethrin and deltamethrin, are used to control malaria. DDT is estrogenic and its breakdown product DDE is anti-androgenic; cypermethrin and deltamethrin can also disrupt androgen pathways. We examined the relationship between maternal exposure to these insecticides during pregnancy and hypospadias among boys participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) in Limpopo Province, South Africa. We measured peripartum levels of p,p'-DDT and p,p'-DDE in maternal serum and urinary pyrethroid metabolites. We conducted urogenital examination on 359 one-year-old boys. A total of 291 (81.0 %) had phimosis, which prevented full urogenital examination, leaving a final sample of 68 boys for determination of the presence of hypospadias. Diagnosis was based on concordance of two independent physicians. We identified hypospadias in 23 of the 68 boys (34 %). Maternal urinary concentrations of cis-DCCA and trans-DCCA metabolites of cypermethrin and other pyrethroids, were associated with an increased risk for hypospadias, but the other metabolite 3-PBA was not (adjusted relative risk per 10-fold increase = 1.58, 95 % CI 1.07–2.34; 1.61, 95 % CI 1.09–2.36; and 1.48, 95 % CI 0.78–2.78, respectively). No associations were found between p,p'-DDT, p,p'-DDE, 3-PBA or cis-DBCA and hypospadias. We observed a high prevalence of hypospadias among boys without phymosis. Boys with higher prenatal exposure to pyrethroid insecticides were at higher risk of hypospadias. Our findings may have global implications given that pyrethroid insecticides are widely used for malaria control, in agriculture and for home use.

Urinary metabolites as a predictive marker for perinatal depression: A secondary analysis of the mothers, Omega-3 &amp; Mental Health Study

Background:Perinatal depression has been associated with unfavorable pregnancy and childhood development outcomes; however, no objective markers exist to identify perinatal mood disorders. We investigated whether metabolites in maternal urine during pregnancy can predict increased depressive symptoms in late pregnancy and postpartum among pregnant women at risk for perinatal depression.Methods:We evaluated metabolomic markers in urine collected at 12–20 and 34–36 weeks’ gestation. We analyzed 49 urinary metabolites using ion pairing reversed-phase liquid chromatography-mass spectrometry. Depressive symptom severity was identified using Beck Depression Inventory (BDI) scores from 105 participants at 12–20 and 34–36 weeks’ gestation, and 6–8 weeks’ postpartum. Mixed model repeated measures analysis evaluated associations between changes in maternal urinary metabolites and BDI scores across pregnancy.Results:Increases in urinary xanthine and hypoxanthine were positively associated with increases in maternal depressive symptoms throughout pregnancy (p = 0.03 and 0.02, respectively). This finding did not persist after false discovery rate correction. None of the urinary metabolites examined were significantly associated with development of postpartum depressive symptoms.Limitations:This study is an exploratory secondary biologic sample analysis from a trial whose sample size was determined by a different primary outcome and expected effect size, which may have limited statistical power to detect associations between urinary metabolites, depressive symptoms, and mood trajectory over time.Conclusions:Increasing concentrations of xanthine and hypoxanthine were associated with increasing depressive symptoms throughout pregnancy. Further research is needed to evaluate the utility of these metabolic markers in identifying women at risk for perinatal depressive symptoms.

Longitudinal associations of pre-pregnancy BMI and gestational weight gain with maternal urinary metabolites: an NYU CHES study.

Background/Objectives:Excessive gestational weight gain (GWG) and pre-pregnancy obesity affect a significant portion of the US pregnant population and are linked with negative maternal and child health outcomes. The objective of this study was to explore associations of pre-pregnancy body mass index (pBMI) and GWG with longitudinally measured maternal urinary metabolites throughout pregnancy.Subjects/Methods:Among 652 participants in the New York University Children’s Health and Environment Study, a longitudinal pregnancy cohort, targeted metabolomics were measured in serially collected urine samples throughout pregnancy. Metabolites were measured at median 10 (T1), 21 (T2), and 29 (T3) weeks gestation using the Biocrates AbsoluteIDQ® p180 Urine Extension kit. Acylcarnitine, amino acid, biogenic amine, phosphatidylcholine, lysophosphatidylcholine, sphingolipid, and sugar levels were quantified. Pregnant people 18 years or older, without type 1 or 2 diabetes and with singleton live births and valid pBMI and metabolomics data were included. GWG and pBMI were calculated using weight and height data obtained from electronic health records. Linear mixed effects models with interactions with time were fit to determine the gestational age-specific associations of categorical pBMI and continuous interval-specific GWG with urinary metabolites. All analyses were corrected for false discovery rate.Results:Participants with obesity had lower long-chain acylcarnitine levels throughout pregnancy and lower phosphatidylcholine and glucogenic amino acids and higher phenylethylamine concentrations in T2 and T3 compared with participants with normal/underweight pBMI. GWG was associated with taurine in T2 and T3 and C5 acylcarnitine species, C5:1, C5-DC, and C5-M-DC, in T2.Conclusions:pBMI and GWG were associated with the metabolic environment of pregnant individuals, particularly in relation to mid-pregnancy. These results highlight the importance of both preconception and prenatal maternal health.

Phthalate Exposure, PPARα Variants, and Neurocognitive Development of Children at Two Years.

Background: The PPARα gene may be crucial to the neurotoxic effect of phthalates. However, epidemiological studies considering the neurodevelopmental influence of phthalates interacting with genetic susceptibility are limited. We hypothesized phthalates could interact with the PPARα gene, synergistically affecting neurocognitive development. Methods: A total of 961 mother-infant pairs were involved in this study. The concentrations of phthalate metabolites in maternal urine during pregnancy were detected. Children’s neurocognitive development was estimated with the Bailey Infant Development Inventory (BSID). Genetic variations in PPARα were genotyped with the Illumina Asian Screening Array. We applied generalized linear regression models to estimate genotypes and phthalate metabolites’ association with children’s neurocognitive development. Results: After adjusting for potential confounders, the mono-n-butyl phthalate (MnBP) concentration was negatively associated with Psychomotor Development Index (PDI) (β = −0.86, 95% CI: −1.67, −0.04). The associations between MnBP and neurocognitive development might be modified by PPARα rs1800246. Compared with low-MnBP individuals carrying rs1800246 GG genotypes, high-MnBP individuals with the AG + AA genotype had a higher risk of neurocognitive developmental delay, with the odds ratio of 2.76 (95% CI:1.14, 6.24). Conclusions: Our current study revealed that prenatal exposure to MnBP was negatively correlated with children’s neurocognitive development, and PPARα rs1800246 might modify the association.