Fetal and Infancy Exposure to Phenols, Parabens, and Phthalates and Anthropometric Measurements up to 36 Months, in the Longitudinal SEPAGES Cohort.

BACKGROUND: Endocrine-disrupting chemicals may play a role in adiposity development during childhood. Until now literature in this scope suffers from methodologic limitations in exposure assessment using one or few urine samples and missing assessment during the infancy period. OBJECTIVES: We investigated the associations between early-life exposure to quickly metabolized chemicals and post-natal growth, relying on repeated within-subject urine collections over pregnancy and infancy. METHODS: We studied the associations of four phenols, four parabens, seven phthalates, and one nonphthalate plasticizer from weekly pooled urine samples collected from the mother during second and third trimesters (median 18 and 34 gestational weeks, respectively) and infant at 2 and 12 months of age, and child growth until 36 months. We relied on repeated measures of height, weight and head circumference from study visits and the child health booklet to predict growth outcomes at 3 and 36 months using the Jenss-Bayley nonlinear mixed model. We assessed associations with individual chemicals using adjusted linear regression and mixtures of chemicals using a Bayesian kernel machine regression model. RESULTS: The unipollutant analysis revealed few associations. Bisphenol S (BPS) at second trimester was positively associated with all infant growth parameters at 3 and 36 months, with similar patterns between exposure at third trimester and all infant growth parameters at 3 months. Mono-n-butyl phthalate (MnBP) at 12 months was positively associated with body mass index (BMI), weight, and head circumference at 36 months. Mixture analysis revealed positive associations between exposure at 12 months and BMI and weight at 36 months, with MnBP showing the highest effect size within the mixture. CONCLUSIONS: This study suggests that exposure in early infancy may be associated with increased weight and BMI in early childhood, which are risk factors of obesity in later life. Furthermore, this study highlighted the impact of BPS, a compound replacing bisphenol A, which has never been studied in this context. https://doi.org/10.1289/EHP13644.

The associations between maternal and fetal exposure to endocrine-disrupting chemicals and asymmetric fetal growth restriction: a prospective cohort study.

Recent evidence has revealed associations between endocrine-disrupting chemicals (EDCs) and placental insufficiency due to altered placental growth, syncytialization, and trophoblast invasion. However, no epidemiologic study has reported associations between exposure to EDCs and asymmetric fetal growth restriction (FGR) caused by placenta insufficiency. The aim of this study was to evaluate the association between EDC exposure and asymmetric FGR. This was a prospective cohort study including women admitted for delivery to the Maternal Fetal Center at Seoul St. Mary's Hospital between October 2021 and October 2022. Maternal urine and cord blood samples were collected, and the levels of bisphenol-A (BPA), monoethyl phthalates, and perfluorooctanoic acid in each specimen were analyzed. We investigated linear and non-linear associations between the levels of EDCs and fetal growth parameters, including the head circumference (HC)/abdominal circumference (AC) ratio as an asymmetric parameter. The levels of EDCs were compared between fetuses with and without asymmetric FGR. Of the EDCs, only the fetal levels of BPA showed a linear association with the HC/AC ratio after adjusting for confounding variables (ß = 0.003, p < 0.05). When comparing the normal growth and asymmetric FGR groups, the asymmetric FGR group showed significantly higher maternal and fetal BPA levels compared to the normal growth group (maternal urine BPA, 3.99 µg/g creatinine vs. 1.71 µg/g creatinine [p < 0.05]; cord blood BPA, 1.96 µg/L vs. -0.86 µg/L [p < 0.05]). In conclusion, fetal exposure levels of BPA show linear associations with asymmetric fetal growth patterns. High maternal and fetal exposure to BPA might be associated with asymmetric FGR.

Non-persistent endocrine disrupting chemical mixtures and uterine leiomyomata in the study of environment, lifestyle and fibroids (SELF).

BACKGROUND: Results of studies investigating associations between individual endocrine-disrupting chemicals (EDCs) and incidence of uterine leiomyomata (UL), a hormone-dependent gynecological condition, have been inconsistent. However, few studies have evaluated simultaneous exposure to a mixture of EDCs with UL incidence. METHODS: We conducted a case-cohort analysis (n = 708) of data from the Study of the Environment, Lifestyle and Fibroids (SELF), a prospective cohort study. Participants were aged 23-35 years at enrollment, had an intact uterus, and identified as Black or African American. We measured biomarker concentrations of 21 non-persistent EDCs, including phthalates, phenols, parabens, and triclocarban, in urine collected at baseline, 20-month, and 40-month clinic visits. We ascertained UL incidence and characteristics using ultrasounds at baseline and approximately every 20 months through 60 months. We used probit Bayesian Kernel Machine Regression (BKMR-P) to evaluate joint associations between EDC mixtures with cumulative UL incidence. We estimated the mean difference in the probit of UL incidence over the study period, adjusting for baseline age, education, years since last birth, parity, smoking status and body mass index. We converted probit estimates to odds ratios for ease of interpretation. RESULTS: We observed that urinary concentrations of the overall EDC mixture were inversely associated with UL incidence in the overall mixtures model, with the strongest inverse associations at the 70th percentile of all biomarkers compared with their 50th percentile (odds ratio = 0.59; 95% confidence interval: 0.36, 0.96). Strongest contributors to the joint association for the mixture were bisphenol S (BPS), ethyl paraben (EPB), bisphenol F (BPF) and mono (2-ethyl-5-carboxypentyl) phthalate (MECPP), which each demonstrated inverse associations except for MECPP. There was suggestive evidence of an interaction between MECPP and EPB. CONCLUSION: In this prospective ultrasound study, we observed evidence of an inverse association between the overall mixture of urinary biomarker concentrations of non-persistent EDCs with UL incidence.

Associations of dichlorophenols, trichlorophenols, and ortho-phenylphenol with the risk and prognosis of diabetes and prediabetes: A population-based study.

2,4-dichlorophenol (2,4-DCP), 2,5-DCP, 2,4,5-trichlorophenol (2,4,5-TCP), 2,4,6-TCP, and ortho-phenylphenol (OPP) are widely present in the environment. However, their associations with risk and prognosis of diabetes and prediabetes remains unclear. We investigated the associations of these five phenols with the risk of diabetes and prediabetes, and with all-cause and cardiovascular disease (CVD) mortality, in adults with diabetes or prediabetes (n=6419). Information on diabetes and prediabetes indicators, and mortality data was collected from the National Health and Nutrition Examination Survey. Logistic and Cox regression models were used to explore the associations of the five phenols with risk and prognosis of diabetes and prediabetes. Participants in the highest urinary 2,4-DCP and 2,5-DCP tertiles had higher odds of diabetes [adjusted odds ratio (aOR), 1.34, 95 % confidence interval (CI): 1.10, 1.62; aOR, 1.29, 95 % CI: 1.07, 1.56, respectively] than those in the lowest tertiles. Participants with urinary OPP concentrations above the limit of detection (LOD), but below median had an aOR of 1.25 (95 % CI: 1.08, 1.46) for prediabetes compared to those with concentrations below the LOD. In adults with diabetes, the highest 2,4-DCP and 2,5-DCP tertiles were associated with all-cause mortality [adjusted hazard ratio (aHR), 1.49; 95 % CI: 1.08, 2.06; aHR, 1.49; 95 % CI: 1.08, 2.05, respectively] and CVD mortality (aHR, 2.58; 95 % CI: 1.33, 4.97; aHR, 1.96; 95 % CI: 1.06, 3.60, respectively) compared with the lowest tertiles. Compared with 2,4,5-TCP concentrations below the LOD, those above median were associated with all-cause mortality (aHR: 1.75; 95 % CI: 1.24, 2.48) and CVD mortality (aHR: 2.34; 95 % CI: 1.19, 4.63) in adults with prediabetes. Furthermore, the associations between these phenols and mortality were strengthened in some subgroups. Environmental exposure to 2,4-DCP, 2,5-DCP, 2,4,5-TCP, and OPP increases the risk or adverse prognosis of diabetes or prediabetes in adults in the US. Further studies are required to confirm these findings.

Cholesterol mediates the effects of single and multiple environmental phenols in urine on obesity.

BACKGROUND: Overweight and obesity are among the leading chronic diseases worldwide. Environmental phenols have been renowned as endocrine disruptors that contribute to weight changes; however, the effects of exposure to mixed phenols on obesity are not well established. METHODS: Using data from adults in National Health and Nutrition Examination Survey, this study examined the individual and combined effects of four phenols on obesity. A combination of traditional logistic regression and two mixed models (weighted quantile sum (WQS) regression and Bayesian kernel-machine regression (BKMR)) were used together to assess the role of phenols in the development of obesity. The potential mediation of cholesterol on these effects was analyzed through a parallel mediation model. RESULTS: The results demonstrated that solitary phenols except triclosan were inversely associated with obesity (P-value < 0.05). The WQS index was also negatively correlated with general obesity (ß: 0.770, 95% CI: 0.644-0.919, P-value = 0.004) and abdominal obesity (ß: 0.781, 95% CI: 0.658-0.928, P-value = 0.004). Consistently, the BKMR model demonstrated the significant joint negative effects of phenols on obesity. The parallel mediation analysis revealed that high-density lipoprotein mediated the effects of all four single phenols on obesity, whereas low-density lipoprotein only mediated the association between benzophenol-3 and obesity. Moreover, Cholesterol acts as a mediator of the association between mixed phenols and obesity. Exposure to single and mixed phenols significantly and negatively correlated with obesity. Cholesterol mediated the association of single and mixed environmental phenols with obesity. CONCLUSIONS: Assessing the potential public health risks of mixed phenols helps to incorporate this information into practical health advice and guidance.

Feasibility of sulfated BPA and BPS as wastewater-based epidemiology biomarkers: Insights from wastewater and reported human urine analysis.

In wastewater-based epidemiology (WBE), the selection of appropriate biomarkers presents a significant challenge. Recently, sulfated bisphenols have garnered attention as potential WBE biomarkers due to their increased stability in wastewater compared to glucuronide conjugates. This study aims to comprehensively assess the feasibility of employing sulfated BPA and BPS as WBE biomarkers by analyzing both WBE and human biomonitoring data. To conduct this research, wastewater samples were collected from six domestic wastewater treatment plants in Guangzhou, China, and urinary concentration of BPA and BPS were obtained from peer-reviewed literature. The results revealed that mean urinary concentrations of BPA and BPS, calculated using Monte Carlo simulations, significantly exceeded those reported in human biomonitoring studies. Furthermore, the per capita mass load ratio of sulfated BPA and BPS in human urine to the mass load in wastewater was found to be below 10 %. This outcome suggests that the excretion of BPA-S and BPS-S in urine does not make a substantial contribution to wastewater, hinting at the existence of other notable sources. Consequently, our study concludes that sulfated BPA-S and BPS-S are not suitable candidates as WBE biomarkers. This work provides a referenceable analytical framework for evaluating the feasibility of WBE biomarkers and emphasizes the necessity for caution when utilizing WBE to assess human exposure to chemicals.

Early childhood exposure to environmental phenols and parabens, phthalates, organophosphate pesticides, and trace elements in association with attention deficit hyperactivity disorder (ADHD) symptoms in the CHARGE study.

BACKGROUND: A growing body of literature investigated childhood exposure to environmental chemicals in association with attention-deficit/hyperactivity disorder (ADHD) symptoms, but limited studies considered urinary mixtures of multiple chemical classes. This study examined associations of concurrent exposure to non-persistent chemicals with ADHD symptoms in children diagnosed with autism spectrum disorder (ASD), developmental delay (DD), and typical development (TD). METHODS: A total of 549 children aged 2-5 years from the Childhood Autism Risks from Genetics and Environment (CHARGE) case-control study were administered the Aberrant Behavior Checklist (ABC). This study focused on the ADHD/noncompliance subscale and its two subdomains (hyperactivity/impulsivity, inattention). Sixty-two chemicals from four classes (phenols/parabens, phthalates, organophosphate pesticides, trace elements) were quantified in child urine samples, and 43 chemicals detected in > 70% samples were used to investigate their associations with ADHD symptoms. Negative binomial regression was used for single-chemical analysis, and weighted quantile sum regression with repeated holdout validation was applied for mixture analysis for each chemical class and all chemicals. The mixture analyses were further stratified by diagnostic group. RESULTS: A phthalate metabolite mixture was associated with higher ADHD/noncompliance scores (median count ratio [CR] = 1.10; 2.5th, 97.5th percentile: 1.00, 1.21), especially hyperactivity/impulsivity (median CR = 1.09; 2.5th, 97.5th percentile: 1.00, 1.25). The possible contributors to these mixture effects were di-2-ethylhexyl phthalate (DEHP) metabolites and mono-2-heptyl phthalate (MHPP). These associations were likely driven by children with ASD as these were observed among children with ASD, but not among TD or those with DD. Additionally, among children with ASD, a mixture of all chemicals was associated with ADHD/noncompliance and hyperactivity/impulsivity, and possible contributors were 3,4-dihydroxy benzoic acid, DEHP metabolites, MHPP, mono-n-butyl phthalate, and cadmium. CONCLUSIONS: Early childhood exposure to a phthalate mixture was associated with ADHD symptoms, particularly among children with ASD. While the diverse diagnostic profiles limited generalizability, our findings suggest a potential link between phthalate exposure and the comorbidity of ASD and ADHD.

Distribution and potential risk factors of bisphenol a in serum and urine among Chinese from 2004 to 2019.

Background: Bisphenol A (BPA) is an oil-derived, large-market volume chemical with endocrine disrupting properties and reproductive toxicity. Moreover, BPA is frequently used in food contact materials, has been extensively researched recently, and widespread exposure in the general population has been reported worldwide. However, national information on BPA levels in general Chinese people is lacking. Methods: This study collected and analyzed 145 (104 in urine and 41 in serum) research articles published between 2004 and 2021 to reflect the BPA internal exposure levels in Chinese populations. The Monte Carlo simulation method is employed to analyze and estimate the data in order to rectify the deviation caused by a skewed distribution. Results: Data on BPA concentrations in urine and serum were collected from 2006 to 2019 and 2004 to 2019, respectively. Urinary BPA concentrations did not vary significantly until 2017, with the highest concentration occurring from 2018 to 2019 (2.90 ng/mL). The serum BPA concentration decreased to the nadir of 1.07 ng/mL in 2011 and gradually increased to 2.54 ng/mL. Nationally, 18 provinces were studied, with Guangdong (3.50 ng/mL), Zhejiang (2.57 ng/mL), and Fujian (2.15 ng/mL) having the highest urine BPA levels. Serum BPA was investigated in 15 provinces; Jiangsu (9.14 ng/mL) and Shandong (5.80 ng/mL) were relatively high. The results also indicated that males' urine and serum BPA levels were higher than females, while the BPA levels in children were also higher than in adults (p < 0.001). Furthermore, the volume of garbage disposal (r = 0.39, p < 0.05), household sewage (r = 0.34, p < 0.05), and waste incineration content (r = 0.35, p < 0.05) exhibited a strong positive connection with urine BPA levels in Chinese individuals. Conclusion: Despite using a data consolidation approach, our study found that the Chinese population was exposed to significant amounts of BPA, and males having a higher level than females. Besides, the levels of BPA exposure are influenced by the volume of garbage disposal, household sewage, and waste incineration content.

Identifying critical windows of prenatal phenol, paraben, and pesticide exposure and child neurodevelopment: Findings from a prospective cohort study.

BACKGROUND: This study aimed to investigate how exposure to a mixture of endocrine disrupting chemicals (EDCs) during two points in pregnancy affects early childhood neurodevelopment. METHODS: We analyzed publicly-available data from a high-risk cohort of mothers and their children (2007-2014) that measured six EDCs including methyl-, ethyl- and propyl parabens (MEPB, ETPB, PRPB), Bisphenol-A (BPA), 3,5,6-trichloro-2-pyridinol (TCPy), 3-phenoxybenzoic acid (3-PBA) in prenatal urine samples during the second and third trimesters. Neurodevelopmental scores were assessed using Mullen Scales of Early Learning (MSEL) at age 3. We used mean field variational Bayes for lagged kernel machine regression (MFVB-LKMR) to investigate the association between trimester-specific co-exposure to the six EDCs and MSEL scores at age 3, stratified by sex. RESULTS: The analysis included 130 children. For females, the relationship between BPA and 3PBA with MSEL score varied between the two trimesters. In the second trimester, effect estimates for BPA were null but inversely correlated with MSEL score in the third trimester. 3PBA had a negative relationship with MSEL in the second trimester and positive correlation in the third trimester. For males, effect estimates for all EDCs were in opposing directions across trimesters. MFVB-LKMR analysis identified significant two-way interaction between EDCs for MSEL scores in both trimesters. For example, in females, the MSEL scores associated with increased exposure to TCPy were 1.75 units (95%credible interval -0.04, -3.47) lower in the 2nd trimester and 4.61 (95%CI -3.39, -5.84) lower in the third trimester when PRPB was fixed at the 75th percentile compared to when PRPB was fixed at the 25th percentile. CONCLUSION: Our study provides evidence that timing of EDC exposure within the prenatal period may impact neurodevelopmental outcomes in children. More of these varying effects were identified among females. Future research is needed to explore EDC mixtures and the timing of exposure during pregnancy to enhance our understanding of how these chemicals impact child health.

Bisphenol A and cardiometabolic risk in adolescents: Data from the Generation XXI cohort.

BACKGROUND AND AIMS: Bisphenol A (BPA), an endocrine disruptor widely used in food contact materials, has been linked to a worse health profile. This study intends to estimate the association between BPA exposure and cardiometabolic patterns at adolescence. METHODS AND RESULTS: Data from the Portuguese population-based birth cohort Generation XXI at the age of 13 were used (n = 2386 providing 3-day food diaries and fasting blood samples). BPA exposure was measured in 24-h urine from a subsample (n = 206) and then predicted in all participants using a random forest method and considering dietary intake from diaries. Three cardiometabolic patterns were identified (normal, modified lipid profile and higher cardiometabolic risk) using a probabilistic Gaussian mixture model. Multinomial regression models were applied to associate BPA exposure (lower, medium, higher) and cardiometabolic patterns, adjusting for confounders. The median BPA exposure was 1532 ng/d, corresponding to 29.4 ng/kg/d. Adolescents higher exposed to BPA (compared to medium and lower levels) had higher BMI z-score (kg/m2) (0.68 vs. 0.39 and 0.52, respectively; p = 0.008), higher levels of body fat (kg) (16.3 vs. 13.8 and 14.6, respectively; p = 0.002), waist circumference (76.2 vs. 73.7 and 74.9, respectively; p = 0.026), insulinemia (ug/mL) (14.1 vs. 12.7 and 13.1, respectively; p = 0.039) and triglyceridemia (mg/dL) (72.7 vs. 66.1 and 66.5, respectively; p = 0.030). After adjustment, a significant association between higher BPA and a higher cardiometabolic risk pattern was observed (OR: 2.55; 95%CI: 1.41, 4.63). CONCLUSION: Higher BPA exposure was associated with a higher cardiometabolic risk pattern in adolescents, evidencing the role of food contaminants in health.

Urinary concentrations of bisphenol A and its alternatives: Potential predictors of and associations with antral follicle count among women from an infertility clinic in Northern China.

BACKGROUND: Experimental studies have suggested exposure to bisphenol A (BPA) and its alternatives, such as bisphenol F (BPF) and bisphenol S (BPS), may exert adverse effects on ovarian reserve, but human evidence is limited. Moreover, the potential predictors of exposure to bisphenols among women seeking infertility treatment have not been reported. OBJECTIVE: To explore whether individual or mixture of BPA, BPF, and BPS were related to antral follicle count (AFC), and further identify the predictors of exposure to bisphenols among women seeking assisted reproductive treatment. METHODS: A total of 111 women from a reproductive center in Shenyang, China were enrolled in this study from September 2020 to February 2021. The concentrations of urinary BPA, BPF, and BPS were measured using ultra-high-performance liquid chromatography-triple quadruple mass spectrometry (UHPLC-MS/MS). AFC was measured by two infertility physicians through transvaginal ultrasonography on the 2-5 days of a natural cycle. Demographic characteristics, dietary habits, and lifestyles were obtained by questionnaires. The associations between individual and mixture of urinary bisphenols concentrations (BPA, BPF, and BPS) and AFC were assessed by the Poisson regression models and the quantile-based g-computation (QGC) model, respectively. The potential predictors of exposure to bisphenols were identified by the multivariate linear regression models. RESULTS: After adjusting for confounders, elevated urinary concentrations of BPA, BPF and BPS were associated with reduced AFC (ß = -0.016; 95%CI: -0.025, -0.006 in BPA; ß = -0.017; 95%CI: -0.029, -0.004 in BPF; ß = -0.128; 95%CI: -0.197, -0.060 in BPS). A quantile increase in the bisphenols mixture was negatively associated with AFC (ß = -0.101; 95%CI: -0.173, -0.030). Intake of fried food had higher urinary concentrations of BPF, BPS, and total bisphenols (∑BPs) than women who did not eat, and age was related to increased urinary BPF concentrations. CONCLUSION: Our findings indicated that exposure to individual BPA, BPF, BPS and bisphenol mixtures were associated with impaired ovarian reserve. Furthermore, the intake of fried food, as identified in this study, could serve as an important bisphenols exposure route for reproductive-aged women.

[Association analysis between mixed exposure to phenols and semen quality].

Phenols such as bisphenols, parabens, and triclosan are common environmental endocrine disruptors. Previous epidemiological studies have suggested that phenols may affect semen quality, but the results were inconsistent. In addition, most existing studies have been limited to the effects of a single chemical compound, ignoring the health effects of mixed exposure to multiple chemicals. Thus, we aimed to explore the associations between individual and mixed exposure to phenols and various semen quality parameters. In this study, a rapid and sensitive method was used to determine 18 phenolic compounds in urine samples of 799 volunteers who donated sperm samples to the Shanghai Human Sperm Bank. A spot urine sample was collected from each subject on the day of their clinic visit and stored at -20 ℃ until testing. Urine samples (200 µL) were extracted and added with 20 µL of an internal standard and 50 µL of ß-glucuronidase solution. The mixtures were then incubated for 12 h at 37 ℃. After hydrolysis, the samples were extracted twice using ethyl acetate (500 µL). The concentrations of the 18 phenolic compounds were measured using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Semen quality parameters were analyzed using a computer-aided semen analyzer. Multiple linear regressions were used to detect the associations between individual phenol exposure and semen quality parameters. In addition, weighted quantile sum (WQS) models were used to explore the associations between mixed-phenol exposure and semen quality parameters. After adjusting for potential covariates, the results of multiple linear regressions showed that exposure to ethyl paraben (EtP) was significantly negatively associated with sperm concentration and total sperm count (P<0.05). In addition, exposure to mixed phenols was significantly associated with decreased sperm concentration; methyl paraben (MeP) and EtP were identified as the main contributors to this decrease. Thus, phenol exposure may be associated with decreased semen quality in young males, particularly with respect to sperm concentration and total sperm count.

Associations of urinary non-persistent endocrine disrupting chemical biomarkers with early-to-mid pregnancy plasma sex-steroid and thyroid hormones.

BACKGROUND/OBJECTIVES: Pregnant women are exposed to numerous endocrine disrupting chemicals (EDCs) that can affect hormonal pathways regulating pregnancy outcomes and fetal development. Thus, we evaluated overall and fetal sex-specific associations of phthalate/replacement, paraben, and phenol biomarkers with sex-steroid and thyroid hormones. METHODS: Illinois women (n = 302) provided plasma for progesterone, estradiol, testosterone, free T4 (FT4), total T4 (TT4), and thyroid stimulating hormone (TSH) at median 17 weeks gestation. Women also provided up-to-five first-morning urine samples monthly across pregnancy (8-40 weeks), which we pooled to measure 19 phthalate/replacement metabolites (reflecting ten parent compounds), three parabens, and six phenols. We used linear regression to evaluate overall and fetal sex-specific associations of biomarkers with hormones, as well as weighted quantile sum and Bayesian kernel machine regression (BKMR) to assess cumulative associations, non-linearities, and chemical interactions. RESULTS: In women of relatively high socioeconomic status, several EDC biomarkers were associated with select hormones, without cumulative or non-linear associations with progesterone, FT4, or TT4. The biomarker mixture was negatively associated with estradiol (only at higher biomarker concentrations using BKMR), testosterone, and TSH, where each 10% mixture increase was associated with -5.65% (95% CI: -9.79, -1.28) lower testosterone and -0.09 µIU/mL (95% CI: -0.20, 0.00) lower TSH. Associations with progesterone, testosterone, and FT4 did not differ by fetal sex. However, in women carrying females, we identified an inverted u-shaped relationship of the mixture with estradiol. Additionally, in women carrying females, each 10% increase in the mixture was associated with 1.50% (95% CI: -0.15, 3.18) higher TT4, whereas in women carrying males, the mixture was associated with -1.77% (95% CI: -4.08, 0.58) lower TT4 and -0.18 µIU/mL (95% CI: -0.33, -0.03) lower TSH. We also identified select chemical interactions. CONCLUSION: Some biomarkers were associated with early-to-mid pregnancy hormones. There were some sex-specific and non-linear associations. Future studies could consider how these findings relate to pregnancy/birth outcomes.

Exposure to biocides and its association with atopic dermatitis among children and adolescents: A population-based cross-sectional study in South Korea.

BACKGROUND: Biocides have emerged as a contributor to the rising cases of atopic dermatitis among children and adolescents. Previous animal studies suggested that phenols, parabens, and pyrethroid insecticides present in these products might play a role in atopic dermatitis. However, there's limited epidemiological evidence confirming the individual or combined effects of exposure to these chemicals on atopic dermatitis in young populations. This study aimed to investigate the association between phenol, paraben, and pyrethroid metabolite levels in urine and atopic dermatitis among Korean children and adolescents METHODS: We analyzed 556 preschool children (3-5 years), 701 schoolchildren (6-11 years), and 731 adolescents (12-17 years) enrolled in the 4th Korean National Environmental Health Survey (KoNEHS) (2018-2020). We used logistic regression and Bayesian kernel machine regression to evaluate the association between atopic dermatitis and individual or mixed exposure to urinary triclosan (TCS), parabens (methylparaben, ethylparaben, propylparaben, and butylparaben), and 3-phenoxybenzoic acid (3-PBA) levels. RESULTS: Urinary TCS levels were positively associated with atopic dermatitis in schoolchildren. When stratified by sex, male schoolchildren exhibited an increasing prevalence of atopic dermatitis as their urinary TCS and 3-PBA levels increased. The combined effect of biocide mixtures on atopic dermatitis was also significantly increased in male schoolchildren, with TCS as the main contributor. CONCLUSIONS: These study findings suggest that biocides at levels found in Korean children and adolescents affect atopic dermatitis.

Urinary concentrations of environmental phenol among pregnant women in the Japan Environment and Children's Study.

Humans are exposed to various bisphenols, alkylphenols and nitrophenols through dietary intake, food packaging and container materials, indoor and outdoor air/dust. This study aimed to evaluate exposure of Japanese pregnant women to environmental phenols by measuring target compounds in urine samples. From a cohort of the Japan Environment and Children's Study, 4577 pregnant women were selected. Bisphenol A (BPA), bisphenol S (BPS), bisphenol F (BPF), bisphenol AF (BPAF), para-nitrophenol (PNP), 3-methyl-4-nitrophenol (PNMC), branched 4-nonylphenol (4-NP), linear 4-nonylphenol and 4-tert-octylphenol (4-t-OP) were analysed using a high-performance liquid chromatograph coupled to a triple-quadrupole mass spectrometer. The urinary metabolite data were combined with a questionnaire to examine the determinants of phenol exposure by machine learning. The estimated daily intake (EDI) and hazard quotient (HQ) of BPA were calculated. PNP (68.2%) and BPA (71.5%) had the highest detection frequencies, with median concentrations of 0.76 and 0.46 µg/g creatinine, respectively. PNMC, BPS, BPF and 4-NP were determined in 24.9%, 11.9%, 1.3% and 0.4% of samples, respectively, whereas BPAF (0.02%) and 4-t-OP (0.02%) were only determined in a few samples. The PNP concentrations measured in this study were comparable with those reported in previous studies, whereas the BPA concentrations were lower than those reported previously worldwide. The EDI of BPA was 0.014 µg/kg body weight/day. Compared with the tolerable daily intake set by the German Federal Institute for Risk Assessment, the median (95th percentile) HQ was 0.044 (0.2). This indicates that the observed levels of BPA exposure pose a negligible health risk to Japanese pregnant women. Determinants of bisphenol and nitrophenol exposure could not be identified by analysing the questionnaire solely, suggesting that biological measurement is necessary to assess exposure of pregnant women to bisphenols and nitrophenols. This is the first study to report environmental phenol exposure of Japanese pregnant women on a nationwide scale.

Prenatal Exposure to Nonpersistent Environmental Chemicals and Postpartum Depression.

Importance: Postpartum depression (PPD) affects up to 20% of childbearing individuals, and a significant limitation in reducing its morbidity is the difficulty in modifying established risk factors. Exposure to synthetic environmental chemicals found in plastics and personal care products, such as phenols, phthalates, and parabens, are potentially modifiable and plausibly linked to PPD and have yet to be explored. Objective: To evaluate associations of prenatal exposure to phenols, phthalates, parabens, and triclocarban with PPD symptoms. Design, Setting, and Participants: This was a prospective cohort study from 5 US sites, conducted from 2006 to 2020, and included pooled data from 5 US birth cohorts from the National Institutes of Health Environmental Influences on Child Health Outcomes (ECHO) consortium. Participants were pregnant individuals with data on urinary chemical concentrations (phenols, phthalate metabolites, parabens, or triclocarban) from at least 1 time point in pregnancy and self-reported postnatal depression screening assessment collected between 2 weeks and 12 months after delivery. Data were analyzed from February to May 2022. Exposures: Phenols (bisphenols and triclosan), phthalate metabolites, parabens, and triclocarban measured in prenatal urine samples. Main Outcomes and Measures: Depression symptom scores were assessed using the Edinburgh Postnatal Depression Scale (EPDS) or the Center for Epidemiologic Studies Depression Scale (CES-D), harmonized to the Patient-Reported Measurement Information System (PROMIS) Depression scale. Measures of dichotomous PPD were created using both sensitive (EPDS scores ≥10 and CES-D scores ≥16) and specific (EPDS scores ≥13 and CES-D scores ≥20) definitions. Results: Among the 2174 pregnant individuals eligible for analysis, nearly all (>99%) had detectable levels of several phthalate metabolites and parabens. PPD was assessed a mean (SD) of 3 (2.5) months after delivery, with 349 individuals (16.1%) and 170 individuals (7.8%) screening positive for PPD using the sensitive and specific definitions, respectively. Linear regression results of continuous PROMIS depression T scores showed no statistically significant associations with any chemical exposures. Models examining LMW and HMW phthalates and di (2-ethylhexyl) phthalate had estimates in the positive direction whereas all others were negative. A 1-unit increase in log-transformed LMW phthalates was associated with a 0.26-unit increase in the PROMIS depression T score (95% CI, -0.01 to 0.53; P = .06). This corresponded to an odds ratio (OR) of 1.08 (95% CI, 0.98-1.19) when modeling PPD as a dichotomous outcome and using the sensitive PPD definition. HMW phthalates were associated with increased odds of PPD (OR, 1.11; 95% CI, 1.00-1.23 and OR, 1.10; 95% CI, 0.96-1.27) for the sensitive and specific PPD definitions, respectively. Sensitivity analyses produced stronger results. Conclusions and Relevance: Phthalates, ubiquitous chemicals in the environment, may be associated with PPD and could serve as important modifiable targets for preventive interventions. Future studies are needed to confirm these observations.

Prenatal to preschool exposure of nonylphenol and bisphenol A exposure and neurodevelopment in young children.

BACKGROUND: Nonylphenol (NP) and bisphenol A (BPA) are produced in large quantities worldwide as multipurpose agents. However, studies on relations between NP and BPA exposure and childhood neurodevelopment are few, and the results are inconsistent. This study aimed to investigate associations between prenatal and early childhood NP and BPA exposure and neurodevelopment in mother-child pairs. METHODS: Pregnant women at 27-38 weeks' gestation were recruited, as were children 2-3 years of age (n = 94) and 4-6 years of age (n = 56) years. Urine was collected to assess NP and BPA exposure. Bayley Scales of Infant and Toddler Development (3rd edition; Bayley-III), Wechsler Preschool and Primary Scale of Intelligence (4th edition), and the Full Scale Intelligence Quotient (WPPSI-IV-FSIQ) were used to assess the neurodevelopment of the children. RESULTS: The detection rate and concentration of NP and BPA in the urine of children 4-6 years old were higher than in those 2-3 years old. Children were divided into a high concentration group (3rd tertile) and a reference group (1st and 2nd tertiles) based on natural log-transformed urine concentration of NP and BPA. Girls' Bayley-III motor scores in the high concentration group were higher than those of the BPA reference group of urine of mothers (ß = 6.85, 95% confidence interval [CI]: 1.58-12.13). Boys' FSIQ in the higher concentration group were significantly lower than those in children 2-3 years old in the NP reference group (ß = -11.29, 95% CI: -18.62 to -3.96) (all, p < 0.05). CONCLUSIONS: Prenatal and childhood exposure to NP and BPA may have different effects on the neurodevelopment of young children, and there are no consistent effects between boys and girls.

Repeated measurements and mixture effects of urinary bisphenols, parabens, polycyclic aromatic hydrocarbons, and other chemicals on biomarkers of oxidative stress in pre- and postpartum women.

The association between oxidative stress and exposure to bisphenols, parabens, phenols, polycyclic aromatic hydrocarbons (PAH), and volatile organic compounds (VOCs) has been investigated by many in vitro and in vivo studies. However, most of these findings are based on cross-sectional studies, as a result of which the combined effects of these compounds have been rarely analyzed. In this study, our objective was to assess urinary bisphenols, parabens, PAHs, and VOCs, in relation to oxidative stress during pre-and postpartum periods, analyze the association between these chemicals and oxidative stress via repeated measurements using a linear mixed model (LMM), and evaluate the combined effects exerted by these chemicals on oxidative stress using Bayesian Kernel Machine Regression (BKMR). A total 529 urine samples were collected from 242 pregnant women during the 1st and 2nd trimesters, as well as postpartum follow-ups. Three bisphenols, four parabens, benzopheone-3 (BP-3), triclosan (TCS), four PAHs, two VOCs, and 3- phenoxy-benzoic acid (3-PBA) were analyzed. We also measured 8-hydroxydeoxyguanosine (8-OHdG) and malondialdehyde (MDA), which serve as oxidative stress biomarkers in maternal urine samples. During this period, 8-OHdG decreased steadily, whereas MDA increased during pregnancy and decreased after childbirth. LMM indicated that Bisphenol A, Prophyl-paraben, BP-3, and 1-hydroxypyrene (1-OHP) showed a significant association with increased MDA levels. The BKMR models revealed that the mixture effect exerted by these 16 chemicals had changed MDA levels, which indicate oxidative stress, and that both Butyl Paraben (BP) and 1-hydroxypyrene (1-OHP) had contributed to such oxidative stress. Mixtures of each subgroup (bisphenols, parabens, and PAHs) were associated with increased MDA levels. These findings suggest that exposure to some phenols and PAHs during pre- and post-partum stages may cause oxidative stress, and that exposure to these chemicals should be minimized during this period.

Methodological approaches for the assessment of bisphenol A exposure.

Bisphenol A (BPA) is an endocrine disruptor used in food contact materials, by the application of polycarbonate plastics and epoxy resins. The main objective of this study is to compare the estimate of daily BPA exposure at 13 years of age and in the adult Portuguese population, using different methodological approaches, and assess the associations between this exposure and sociodemographic characteristics. METHODOLOGY: Cross-sectional data of 13-years follow-up from a population-based birth cohort Generation XXI (GXXI) (n = 2804) and from the National Food, Nutrition and Physical Activity Survey (IAN-AF 2015-2016) (n = 3845, ≥18 years old) was used. Dietary information was collected through three food diaries for adolescents and two non-consecutive 24-hour-recalls for adults. To estimate the daily exposure to BPA, three methodological approaches were used. "Food groups attribution" merged the food consumption data with the concentration of BPA in food groups. "Regression tree model" and "random forest" combined food consumption information with urinary BPA, measured in a subsample of 24-hour urine (in adolescents n = 216, and in adults n = 82), both used to predict BPA exposure in the remaining sample. The fit-index of the methodologies was assessed through the root mean square error (RMSE), mean absolute error (MAE) and Spearman correlation coefficient (ρ). Associations between BPA exposure and sociodemographic variables were tested by linear regression models, adjusted for sex, age groups (in adults) and educational level. Tolerable Daily Intake (TDI) of 0.2 ng/kg body weight (bw), recently proposed by the European Food Safety Authority (EFSA), was used for the risk characterization of BPA exposure. RESULTS: The "random forest" was found as the best methodology to estimate the daily BPA exposure (adolescents: RMSE = 0.989, MAE = 0.727, ρ = 0.168; adults: RMSE = 0.193, MAE = 0.147, ρ = 0.250). The median dietary BPA exposure, calculated by "food groups attribution", was 79.1 and 46.1 ng/kg bw/day for adolescents and adults, respectively, while "random forest" estimated a BPA exposure of 26.7 and 38.0 ng/kg bw/day. 99.9% of the Portuguese population presented a daily exposure above TDI. Male adolescents, females and higher educated adults, were those more exposed to BPA. CONCLUSIONS: The estimated daily BPA exposure strongly depends on the methodological approach. Food groups attribution may overestimate the exposure while the random forest appears to be a better methodological approach to estimate BPA exposure. Nevertheless, for all methods, the Portuguese population presented an unsafe BPA exposure by largely exceeding the safe levels proposed by EFSA.

Environment-wide association study to identify exposure pathways of bisphenol A in Korean children and adolescents: Korean National Environmental Health Survey (KoNEHS) 2018-2020.

Bisphenol A (BPA) is an endocrine-disrupting chemical commonly used in manufacturing plastic products. Despite ongoing efforts and regulatory measures, BPA exposure among children persists. This study aimed to identify the modifiable factors associated with urinary BPA levels in Korean children and adolescents. We conducted an environment-wide association study (EWAS) using data from the Korean National Environmental Health Survey (KoNEHS) Cycle 4. This study included 578 preschoolers, 736 school-aged children, and 828 adolescents. A total of 117, 103, and 102 modifiable factors were selected from KoNEHS Cycle 4. Each modifiable factor associated with urinary BPA levels was tested using a multivariable linear regression model. Subsequently, multiple testing corrections were performed using false discovery rate (FDR) estimation. For the validation phase, we used the iteration of the least absolute shrinkage and selection operator (LASSO), a machine learning-based regression analysis. After the validation phase of the LASSO regression, two modifiable factors were identified as being significantly related to urinary BPA levels in preschoolers. Urinary cotinine levels and the use of slime or clay toys were positively associated with urinary BPA levels in preschoolers. However, no significant associations were observed between school-aged children and adolescents. Our results suggest novel exposure pathways to BPA in recent lifestyles and contribute to the development of effective prevention strategies. These modifiable factors provide valuable targets for interventions aimed at reducing BPA exposure in children. Further research is needed to explore additional modifiable factors and confirm our results in larger and more diverse populations.