Vitamin D Deficiency Exacerbates Poor Sleep Outcomes with Endocrine-Disrupting Chemicals Exposure: A Large American Population Study.

Phthalates and bisphenol A are recognized as the predominant endocrine-disrupting substances (EDCs) in the environment, but their impact on sleep health remains unclear. Vitamin D has often been reported to play a role in sleep health and may be affected by endocrine-disrupting compounds. The study utilized data from 5476 individuals in the NHANES project to investigate the correlation between combined exposure to environmental EDCs and sleep duration through modeling various exposures. Furthermore, it emphasizes the importance of vitamin D in the present scenario. Preliminary analyses suggested that vitamin D-deficient individuals generally slept shorter than individuals with normal vitamin D (p < 0.05). Exposure to Mono-ethyl phthalate (MEP), triclosan (TRS), and Mono-benzyl phthalate (MZP), either alone or in combination, was associated with reduced sleep duration and a greater risk of vitamin D deficiency. Individuals with low vitamin D levels exposed to TRS experienced shorter sleep duration than those with normal vitamin D levels (p < 0.05). TRS and MZP were identified as crucial factors in patient outcomes when evaluating mixed exposures (p < 0.05). The results provide new data supporting a link between exposure to EDCs and insufficient sleep length. Additionally, they imply that a vitamin D shortage may worsen the sleep problems induced by EDCs.

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.

Subpopulations of children with multiple chronic health outcomes in relation to chemical exposures in the ECHO-PATHWAYS consortium.

A multimorbidity-focused approach may reflect common etiologic mechanisms and lead to better targeting of etiologic agents for broadly impactful public health interventions. Our aim was to identify clusters of chronic obesity-related, neurodevelopmental, and respiratory outcomes in children, and to examine associations between cluster membership and widely prevalent chemical exposures to demonstrate our epidemiologic approach. Early to middle childhood outcome data collected 2011-2022 for 1092 children were harmonized across the ECHO-PATHWAYS consortium of 3 prospective pregnancy cohorts in six U.S. cities. 15 outcomes included age 4-9 BMI, cognitive and behavioral assessment scores, speech problems, and learning disabilities, asthma, wheeze, and rhinitis. To form generalizable clusters across study sites, we performed k-means clustering on scaled residuals of each variable regressed on study site. Outcomes and demographic variables were summarized between resulting clusters. Logistic weighted quantile sum regressions with permutation test p-values associated odds of cluster membership with a mixture of 15 prenatal urinary phthalate metabolites in full-sample and sex-stratified models. Three clusters emerged, including a healthier Cluster 1 (n = 734) with low morbidity across outcomes; Cluster 2 (n = 192) with low IQ and higher levels of all outcomes, especially 0.4-1.8-standard deviation higher mean neurobehavioral outcomes; and Cluster 3 (n = 179) with the highest asthma (92 %), wheeze (53 %), and rhinitis (57 %) frequencies. We observed a significant positive, male-specific stratified association (odds ratio = 1.6; p = 0.01) between a phthalate mixture with high weights for MEP and MHPP and odds of membership in Cluster 3 versus Cluster 1. These results identified subpopulations of children with co-occurring elevated levels of BMI, neurodevelopmental, and respiratory outcomes that may reflect shared etiologic pathways. The observed association between phthalates and respiratory outcome cluster membership could inform policy efforts towards children with respiratory disease. Similar cluster-based epidemiology may identify environmental factors that impact multi-outcome prevalence and efficiently direct public policy efforts.

The impact of follicular fluid phthalate metabolites on the ovarian reserve and ovarian function in Indian women undergoing intracytoplasmic sperm injection.

OBJECTIVE: To investigate the adverse effects of phthalate-induced ovarian toxicity on the ovarian reserve and ovarian function. To assess whether the accumulation of higher levels of selected phthalate metabolites in the follicular fluid (FF) of Indian women undergoing intracytoplasmic sperm injection (ICSI) was associated with a decline in their antral follicle count (AFC) and/or serum antimüllerian hormone (AMH) levels, suggesting a negative impact on the ovarian reserve. To evaluate the effects of follicular phthalate metabolites on peak serum estradiol (E2) levels and the total number of oocytes and mature metaphase II (MII) stage oocytes retrieved to assess the impact of phthalate toxicity on ovarian function. DESIGN: A subanalysis of an ongoing prospective cohort study was conducted to examine the association between the levels of six phthalate metabolites, namely, mono-n-butyl phthalate (MBP), mono-ethyl phthalate (MEP), mono-isononyl phthalate (MiNP), mono-isodecyl phthalate (MiDP), mono(2-ethyl-5-oxohexyl) phthalate, and mono(2-ethyl-5-hydroxyhexyl) phthalate, in the FF of Indian women undergoing ICSI and their ovarian reserve markers (AFC and serum AMH levels). To investigate the association of these follicular phthalate metabolite levels with the peak E2 levels and the total number of oocytes and number of MII stage oocytes retrieved. SETTING: In vitro fertilization center in a referral hospital in India. PATIENT(S): A total of 245 consenting Indian women who had undergone oocyte retrieval between April 2017 and mid-March 2020 were included. Each woman contributed one FF sample to the study. This was screened for six phthalate metabolites. The samples were collected before the coronavirus disease 2019 pandemic. INTERVENTION(S): Using liquid chromatography-tandem mass spectrometry, the total levels of six phthalate metabolites were quantified in the FF of 245 women. Using linear regression models that were unadjusted and adjusted for maternal age and body mass index (BMI), we evaluated the association between the follicular metabolites in these women and their AFC, serum AMH levels, peak E2 levels, total number of oocytes, and MII stage oocytes. MAIN OUTCOME MEASURE(S): To evaluate the impact of phthalate-induced ovarian toxicity on the ovarian reserve and ovarian function in Indian women undergoing ICSI by studying their accumulated levels in their FF. RESULT(S): For MiNP (a metabolite of di-isononyl phthalate), in linear regression models adjusted for age and BMI, we found that with increasing quartiles of follicular MiNP, there was a significant trend in the decrease in mean AFC (P-trend = 0.023) and a suggestive trend in the decrease in mean serum AMH levels (P-trend = 0.077). For MiDP (a metabolite of di-isodecyl phthalate), in the unadjusted regression model, we found that with increasing quartiles of follicular MiDP, there was a significant trend in the decrease in mean serum AMH levels (P-trend = 0.045). For MBP (a metabolite of dibutyl phthalate), in linear regression models adjusted for age and BMI, we found that with increasing quartiles of follicular MBP, there were significant trends in the decrease in the mean number of total oocytes retrieved (P-trend = 0.003), a decrease in the mean number of MII stage oocytes retrieved, (P-trend = 0.003) and a decrease in the mean peak E2 levels (P-trend = 0.016). Although we found that with increasing quartiles of follicular mono(2-ethyl-5-oxohexyl) phthalate there was a decrease in the mean number of total and MII stage oocytes retrieved and higher follicular MEP levels were negatively associated with the mean AFC and serum AMH levels, neither trend was statistically significant. We also found that although follicular MEP levels did not show an adverse impact on ovarian function, follicular mono(2-ethyl-5-hydroxyhexyl) phthalate levels did not show an adverse impact on both the ovarian reserve and function. CONCLUSION: In this study of 245 Indian women, higher accumulated FF levels of MiNP and MiDP were negatively associated with AFC and serum AMH levels, suggesting an adverse effect on the ovarian reserve. Higher accumulated FF levels of MBP were negatively associated with the total number of oocytes, MII stage oocytes, and peak E2 values, suggesting a negative impact on ovarian function. Although we found that phthalate-induced ovarian toxicity was statistically significant for selected phthalate metabolites, the role of the cumulative effect of multiple phthalates in the ovarian microenvironment cannot be ruled out and needs to be investigated further.

Food packaging and endocrine disruptors.

OBJECTIVES: Narrative review evaluating food contamination by endocrine disruptors present in food packaging. DATA SOURCE: The terms "endocrine disruptors" and "food packaging" were used in combination in the PubMed, MEDLINE and SciELO databases, evaluating studies, in humans, published in Portuguese, English, French and Spanish between 1990 and 2023. DATA SYNTHESIS: Packaging, especially those made from plastic or recycled material, is an important source of food contamination by endocrine disruptors. Bisphenols and phthalates are the endocrine disruptors most frequently associated with food contamination from packaging. However, many unknown substances and even those legally authorized can cause harm to health when exposure is prolonged or when substances with additive effects are mixed. Furthermore, the discarding of packaging can cause contamination to continue into the environment. CONCLUSION: Although packaging materials are essential for the transport and storage of food, many of them are associated with chemical contamination. As it is not possible to exclude them from our routine, it is important to develop research aimed at identifying the endocrine disruptors present in them, including the effects of chronic exposure; and that regulatory agencies and industry come together to reduce or prevent this risk. Additionally, consumers must be instructed on how to purchase products, handle them and prepare them to reduce the migration of chemical substances into food.

Racial and Ethnic Disparities in Phthalate Exposure and Preterm Birth: A Pooled Study of Sixteen U.S. Cohorts.

BACKGROUND: Phthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth. OBJECTIVES: We investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b) exposure-response models stratified by race and ethnicity. METHODS: We pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate-adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity-stratified logistic regression to characterize associations between phthalate metabolites and preterm birth. RESULTS: In comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): -34%, 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: -19%, 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono-n-butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants. CONCLUSIONS: Phthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831.

Maternal concentrations of phthalates and Attention-Deficit Hyperactivity Disorder (ADHD-) related symptoms in children aged 2 to 4 years from Odense child cohort.

BACKGROUND: Phthalates are endocrine disrupting chemicals used in everyday consumer products. Several epidemiological studies have examined the association between prenatal phthalate concentration and Attention-Deficit Hyperactivity Disorder (ADHD) in offspring, but the findings have been inconclusive. OBJECTIVES: To investigate the association between maternal urinary concentrations of phthalate metabolites during pregnancy and ADHD related symptoms in children at 2 to 4 years in a large prospective cohort. METHODS: In the Odense Child Cohort from Denmark were women recruited in early pregnancy from 2010 to 2012. Phthalate concentrations were measured in urine samples collected in 3rd trimester and separated into low and high weight phthalates. Parents filled in the Child Behavior Checklist for ages 1.5 to 5 years (CBCL/1½-5), including a 6-item ADHD symptom scale at children aged 2 to 4 years. Data were analysed by use of adjusted negative binomial regression. RESULTS: A total of 658 mother-child pairs were included. Urinary phthalate metabolite concentrations were generally low compared to previous cohorts. A doubling in maternal concentration of the low-weighted phthalate metabolite MCPP was significantly associated with lower ADHD symptoms score in children (IRR: 0.95 (95 % CI 0.91-0.98)), strongest in girls (IRR: 0.92 (0.87-0.98)). Sex differences were observed. High maternal phthalate metabolite concentrations were associated with lower ADHD symptom score in girls, significant trends across tertile of MCPP and MnBP (p = 0.018, p = 0.038, respectively). In boys, maternal concentrations of high-molecular-weight phthalates (MBzP, ∑DiNP and ∑DEHP) were associated with an almost significantly higher ADHD symptom score (IRR for a doubling in concentration: 1.04 (95 % CI: 0.99-1.10), IRR: 1.05 (95 % CI: 0.97-1.13), IRR: 1.04 (95 % CI: 0.99-1.10), respectively). CONCLUSION: Maternal concentration of the low-weighted phthalate metabolite MCPP was significantly associated with a lower ADHD symptom score in children, strongest in girls. Maternal concentrations of high-molecular-weight phthalates were associated with non-significant increase in ADHD symptom score in boys.

Prenatal exposure to phthalates and emotional/behavioral development in young children.

INTRODUCTION: Endocrine disrupting chemicals (EDCs) such as phthalates, found in our daily environment, are nowadays suggested to be associated with adverse outcomes. Prenatal exposure was found associated with neurodevelopmental complications such as behavioral difficulties in school age children. AIM: To explore the association between intrauterine exposure to phthalates and emotional/behavioral development of 24 months old toddlers. METHODS: Women were recruited at 11-18 weeks of gestation and provided spot urine samples, analyzed for phthalate metabolites (DEHP, DiNP, MBzBP). Offspring were examined at 24 months of age, using standard maternal report, regarding developmental and behavioral problems (CBCL, ASQ-3, HOME questionnaires) (N = 158). To explore the associations between metabolite levels and developmental outcomes, multivariate GLM analysis (General Linear Model) was used according to tertiles and developmental scores on each developmental outcome. RESULTS: Associations of Di-(2-ethylhexyl) phthalate (DEHP) maternal exposure with behavioral-developmental outcomes were found only in boys. Compared with boys with lower DEHP maternal exposure, boys with high DEHP maternal exposure had lower developmental score in personal social abilities in the ASQ-3 questionnaire (50.68 + 8.06 and 44.14 + 11.02, high and low DEHP, respectively, p = 0.03), and more internalizing problems (for example, emotionally reactive score in high and low DEHP: 53.77 + 7.41 and 50.50 + 1.19, respectively, p = 0.029; anxious or depressed score: 53.38 + 5.01 and 50.75 + 1.34, respectively, p = 0.009; and somatic complaints scores 64.03 + 10.1 and 55.84 + 7.84, respectively, p = 0.003), and externalizing problems (49.28 + 8.59 and 43.33 + 9.11, respectively, p = 0.039). No differences were found in the development and behavior problems between high and low DEHP maternal exposure level in girls. CONCLUSION: Maternal DEHP metabolite concentrations measured in first trimester urine was associated with children's emotional/behavioral developmental problems in 24-months old boys, supporting accumulating evidence of DEHP as a potentially harming chemical and call for environmental attention.

Associations of phthalates, phthalate replacements, and their mixtures with eicosanoid biomarkers during pregnancy.

Humans are exposed to complex mixtures of phthalates. Gestational exposure to phthalates has been linked to preeclampsia and preterm birth through potential pathways such as endocrine disruption, oxidative stress, and inflammation. Eicosanoids are bioactive signaling lipids that are related to a variety of homeostatic and inflammatory processes. We investigated associations between urinary phthalates and their mixtures with plasma eicosanoid levels during pregnancy using the PROTECT cohort in Puerto Rico (N = 655). After adjusting for covariates, we estimated pair-wise associations between the geometric mean of individual phthalate metabolite concentrations across pregnancy and eicosanoid biomarkers using multivariable linear regression. We used bootstrapping of adaptive elastic net regression (adENET) to evaluate phthalate mixtures associated with eicosanoids and subsequently create environmental risk scores (ERS) to represent weighted sums of phthalate exposure for each individual. After adjusting for false-discovery, in single-pollutant analysis, 14 of 20 phthalate metabolites or parent compound indices showed significant and primarily negative associations with multiple eicosanoids. In our mixture analysis, associations with several metabolites of low molecular weight phthalates - DEP, DBP, and DIBP - became prominent. Additionally, MEHHTP and MECPTP, metabolites of a new phthalate replacement, DEHTP, were selected as important predictors for determining the concentrations of multiple eicosanoids from different pathway groups. A unit increase in phthalate ERS derived from bootstrapping of adENET was positively associated with several eicosanoids mainly from Cytochrome P450 pathway. For example, an increase in ERS was associated with 11(S)-HETE (ß = 1.6, 95% CI: 0.020, 3.180), (±)11,12-DHET (ß = 2.045, 95% CI: 0.250, 3.840), 20(S)-HETE (ß = 0.813, 95% CI: 0.147, 1.479), and 9 s-HODE (ß = 2.381, 95% CI: 0.657, 4.104). Gestational exposure to phthalates and phthalate mixtures were associated with eicosanoid levels during pregnancy. Results from the mixture analyses underscore the complexity of physiological impacts of phthalate exposure and call for further in-depth studies to examine these relationships.

Phthalates exposure and pubertal development in a 15-year follow-up birth cohort study in Taiwan.

Purpose: Phthalates are ubiquitous endocrine disruptors that can affect pubertal development in children. The association of fetal and childhood levels of phthalates with pubertal development were explored. Methods: We conduct a population-based birth cohort study to investigate the association between prenatal and childhood exposure to phthalates and pubertal development. Initially, a total of 445 children were recruited from 2000 to 2001, of which 90 children were followed for 15 years which measurements of urine and development assessed at 2, 5, 8, 11, and 14 years. We defined higher Tanner stage as the 14-year-old Tanner stage ≥ 4 and 5 for boys and girls, respectively. A logistic regression analysis was conducted to estimate the crude and adjusted odds ratio of a higher Tanner stage at 14 years old. The Pearson correlation coefficient and multiple linear regression were used to estimate the association of testicular volume, uterine volume, ovarian volume, and blood hormones at 14 years of age with the log-transformed concentration of phthalates at 2, 5, 8, 11, and 14 years. Results: In boys, a significantly different geometric mean of mono-benzyl phthalate (MBzP) was observed in 11-year-olds; 6.82 and 2.96 in the lower Tanner stage group and higher Tanner stage group. In girls, a significant difference in the geometric mean of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) in 11-year-olds and mono-ethyl phthalate (MEP) in 2-year-olds was observed; MEHHP was 32.97 and 18.13 in the lower Tanner stage group and higher Tanner stage group, and MEP was 26.54 and 65.74 in the lower Tanner stage group and higher Tanner stage group, respectively. Uterine volume at 14 years old was negatively associated with several phthalate metabolites (MEHP at 8 years old, MnBP at 8 years old, MBzP at 14 years old, MMP prenatally, MMP at 8 years old, and MEP at 8 years old) after adjusting for covariates. However, no significant correlations were found between phthalate metabolites and ovarian or testicular volume. Conclusion: Phthalate exposure at certain time points may influence the reproductive development of children during puberty; however, further studies should be conducted to determine the causal nature of this association.

Association of urinary phthalate metabolites with all-cause and cardiovascular disease mortality among adults with diabetes mellitus: National Health and Nutrition Examination Survey 2005-2014.

Background: The study regarding phthalate metabolites and mortality among diabetes mellitus (DM) is limited. We aimed to examine the association of urinary phthalate metabolites with all-cause and cardiovascular disease (CVD) mortality among adults with DM. Methods: This study included 8,931 adults from the National Health and Nutrition Examination Survey (NHANES) from 2005-2006 to 2013-2014. Mortality data were linked to National Death Index public access files through December 31, 2015. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidences (CIs) for mortality. Results: We identified 1,603 adults with DM [mean ± SE age, 47.08 ± 0.30 years; 50.5% (833) were men]. Mono-(carboxynonyl) phthalate (MCNP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), and the sum of Di (2-ethylhexyl) phthalate (DEHP) metabolites (∑DEHP) were positively associated with DM (MCNP: OR = 1.53, 95%CI = 1.16-2.01; MECPP: OR = 1.17, 95% CI = 1.03-1.32; ∑DEHP: OR = 1.14, 95% CI = 1.00-1.29). Among DM patients, mono-(3-carboxypropyl) phthalate (MCPP) was associated with a 34% (HR 1.34, 95% CI 1.12-1.61) increased risk of all-cause mortality while the HRs (95%CI) of CVD mortality were 2.02 (1.13-3.64) for MCPP, 2.17 (1.26-3.75) for mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), 2.47 (1.43-4.28) for mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), 2.65 (1.51-4.63) for MECPP, and 2.56 (1.46-4.46) for ∑DEHP, respectively. Conclusion: This study is an academic exploration of the association between urinary phthalate metabolites and mortality among adults with DM, suggesting that exposure to phthalates might be associated with an increased risk of all-cause and CVD mortality in DM. These findings suggest that patients with DM should carefully use plastics products.

Exposure to phthalate metabolites, bisphenol A, and psychosocial stress mixtures and pregnancy outcomes in the Atlanta African American maternal-child cohort.

BACKGROUND: Consumer products are common sources of exposure for phthalates and bisphenol A (BPA), which disrupt the endocrine system. Psychosocial stressors have been shown to amplify the toxic effects of endocrine disruptors but, information is limited among African Americans (AAs), who experience the highest rates of adverse pregnancy outcomes and are often exposed to the highest levels of chemical and non-chemical stressors. We examined the association between an exposure mixture of phthalate metabolites, BPA, and psychosocial stressors with gestational age at delivery and birthweight for gestational age z-scores in pregnant AA women. STUDY DESIGN: Participants were enrolled in the Atlanta African American Maternal-Child Cohort (N = 247). Concentrations of eight phthalate metabolites and BPA were measured in urine samples collected at up to two timepoints during pregnancy (8-14 weeks gestation and 20-32 weeks gestation) and were averaged. Psychosocial stressors were measured using self-reported, validated questionnaires that assessed experiences of discrimination, gendered racial stress, depression, and anxiety. Linear regression was used to estimate individual associations between stress exposures (chemical and psychosocial) and birth outcomes. We leveraged quantile g-computation was used to examine joint effects of chemical and stress exposures on gestational age at delivery (in weeks) and birthweight for gestational age z-scores. RESULTS: A simultaneous increase in all phthalate metabolites and BPA was associated with a moderate reduction in birthweight z-scores (mean change per quartile increase = -0.22, 95% CI = -0.45, 0.0). The association between our exposure mixture and birthweight z-scores became stronger when including psychosocial stressors as additional exposures (mean change per quantile increase = -0.35, 95% CI = -0.61, -0.08). Overall, we found null associations between exposure to chemical and non-chemical stressors with gestational age at delivery. CONCLUSIONS: In a prospective cohort of AA mother-newborn dyads, we observed that increased prenatal exposure to phthalates, BPA, and psychosocial stressors were associated with adverse pregnancy outcomes.

JAK3/STAT5b/PPARγ Pathway Mediates the Association between Di(2-ethylhexyl) Phthalate Exposure and Lipid Metabolic Disorder in Chinese Adolescent Students.

Our previous studies found that di (2-ethylhexyl) phthalate (DEHP) could disorder lipid metabolism in adolescents but the mechanisms underlying this association remained unclear. This study was undertaken to clarify the mediating effect of JAK3/STAT5/PPARγ on disorder lipid levels induced by DEHP in adolescents. We recruited 478 adolescent students (median age 18.1 years). The mRNA expression and DNA methylation levels of JAK3/STAT5/PPARγ were detected by real-time PCR and the MethylTarget, respectively. We used multiple linear regression to analyze the association between DEHP metabolites (MEHP, MEOHP, MEHHP, MECPP, MCMHP, and ΣDEHP) levels, mRNA expression, and DNA methylation levels. The mediating effect of JAK3/STAT5/PPARγ mRNA expression levels was examined by mediation analysis. We found that all DEHP metabolite levels were positively correlated with TC/HDL-C and LDL-C/HDL-C (P < 0.05). The MEOHP level was negatively associated with DNA methylation levels and positively associated with mRNA levels of PPARγ and STAT5b (P < 0.05). The MEHP level was negatively associated with the DNA methylation level and positively associated with the mRNA level of JAK3 (P < 0.05). Higher MEOHP was associated with a higher level of TC/HDL-C, the mediation analysis showed the mediation effect was 17.18% for the JAK3 level, 10.76% for the STAT5b level, and 11% for the PPARγ level. Higher MEHP was associated with a higher level of LDL-C/HDL-C, the mediation effect was 14.49% for the JAK3 level. In conclusion, DEHP metabolites decreased the DNA methylation levels, inducing the increase of the mRNA levels of JAK3/STAT5/PPARγ. In addition, the mRNA levels mediated the association between DEHP exposure and disorder lipid levels.

Cumulative Risk Evaluation of Phthalates Under TSCA.

The U.S. Environmental Protection Agency (EPA) is currently conducting separate Toxic Substances Control Act (TSCA) risk evaluations for seven phthalates: dibutyl phthalate (DBP), butyl benzyl phthalate (BBP), di(2-ethylhexyl) phthalate (DEHP), diisobutyl phthalate (DIBP), dicyclohexyl phthalate (DCHP), di-isodecyl phthalate (DIDP), and diisononyl phthalate (DINP). Phthalates are highly abundant plastic additives used primarily to soften materials and make them flexible, and biomonitoring shows widespread human exposure to a mixture of phthalates. Evidence supports biological additivity of phthalate mixture exposures, including the enhancement of toxicity affecting common biological targets. Risk estimates based on individual phthalate exposure may not be protective of public health. Thus, a cumulative risk approach is warranted. While EPA initially did not signal that it would incorporate cumulative risk assessment (CRA) as part of its current risk evaluation for the seven phthalates, the agency recently announced that it is reconsidering if CRA for phthalates would be appropriate. Based on our review of existing chemical mixtures risk assessment guidance, current TSCA scoping documents for the seven phthalates, and pertinent peer-reviewed literature, we delineate a CRA approach that EPA can easily implement for phthalates. The strategy for using CRA to inform TSCA risk evaluation for existing chemicals is based upon integrative physiology and a common adverse health outcome algorithm for identifying and grouping relevant nonchemical and chemical stressors. We recommend adjustments for how hazard indices (HIs) or margins of exposure (MOEs) based on CRA are interpreted for determining "unreasonable risk" under TSCA.

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 1.81 kg and 0.77 kg 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.

Associations of phthalates with prostate cancer among the US population.

Human exposure to harmful phthalates has raised global health concerns. According to cellular and molecular investigations, phthalates and their metabolites can promote prostate cancer (PCa). Despite being a prevalent cancer afflicting the global male population, the epidemiological association between phthalates and prostate cancer remains understudied. This work aims to investigate whether phthalate metabolites are related to prostate cancer. Moreover, we sought to understand whether their elevated concentrations are associated with increased serum concentrations of prostate-specific antigen (PSA), among non-prostate cancer interviewees. According to National Health and Nutrition Examination Survey (NHANES) data from 2003 to 2010, we screened eligible men aged 20 years or older. Then, crude and multivariate regression models were constructed to assess the relationship. The phthalates significantly related to PCa were analyzed based on variables associated with PCa status and PSA. The molar sum ∑di-2-ethylhexyl phthalate (∑DEHP) was simultaneously associated with increased risk of PCa and increasing PSA concentrations. Among PCa-related phthalates, high molecular weight phthalate metabolites included mono-benzyl phthalate (MBzP) and three metabolites of DEHP. In summary, phthalates are potentially associated with prostate tumorigenesis in the US population. However, additional in-depth prospective studies in different ethnic groups are required to validate the causality between both.

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.

Objective: Prenatal 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. Methods: A 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. Results: Childhood 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. Conclusion: The 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.

Association between recurrent breast cancer and phthalate exposure modified by hormone receptors and body mass index.

The association between phthalate exposure and breast cancer remains controversial. We performed a prospective patient cohort design to explore the interaction between creatinine-corrected urinary phthalate metabolites and hormone receptors as well as body mass index (BMI) on recurrent breast cancer. In this follow-up study, 636 female breast cancer patients and 45 new recurrent cases diagnosed for a total of 1576.68 person-years of follow-up were recruited. Mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively associated with breast cancer recurrence, with adjusted hazard ratio (aHR) 3rd vs. 1st quartile of 0.15 (95% CI 0.04-0.51). The MEOHP presented as a non-monotonic dose-response (NMDR) curve, being U-shaped. In the stratification of hormone receptors, MEOHP still exhibited a U-shaped dose-response curve. The third quartile of MEOHP showed significant lowest recurrent risk in the status of ER-positive (aHR 0.18, 95% CI 0.05-0.66), PR-negative (aHR 0.14, 95% CI 0.03-0.63), and HER2-negative (aHR 0.24, 95% CI 0.08-0.76). Whether in BMI < 25 or in BMI ≥ 25, the third quartile of MEOHP was negatively associated with recurrent breast cancer, and there was a negative interaction on an additive scale between MEOHP and BMI (pinteraction = 0.042). The association between MEOHP and recurrent breast cancer was modified by hormone receptors and BMI.

Medication-Associated Phthalate Exposure and Childhood Cancer Incidence.

BACKGROUND: Human phthalate exposure is widespread through contact with myriad consumer products. Exposure is particularly high through medications formulated with phthalates. Phthalates disrupt normal endocrine signaling and are associated with reproductive outcomes and incidence of some cancers. We measured associations between gestational and childhood medication-associated phthalate exposures and the incidence of childhood cancers. METHODS: We identified all live births in Denmark between 1997 and 2017, including both children and birth mothers. Using drug ingredient data merged with the Danish National Prescription Registry, we measured phthalate exposure through filled prescriptions for mothers during pregnancy (gestational exposure) and for children from birth until age 19 years (childhood exposure). Incident childhood cancers were ascertained from the Danish Cancer Registry, and associations were estimated with Cox regression models. RESULTS: Among 1 278 685 children, there were 2027 childhood cancer cases diagnosed over 13.1 million person-years of follow-up. Childhood phthalate exposure was strongly associated with incidence of osteosarcoma (hazard ratio [HR] = 2.78, 95% confidence interval [CI] = 1.63 to 4.75). We also observed a positive association with incidence of lymphoma (HR = 2.07, 95% CI = 1.36 to 3.14), driven by associations with Hodgkin and non-Hodgkin lymphoma but not Burkitt lymphoma. Associations were apparent only for exposure to low-molecular phthalates, which have purportedly greater biological activity. CONCLUSIONS: Childhood phthalate exposure was associated with incidence of osteosarcoma and lymphoma before age 19 years. Lingering questions include which specific phthalate(s) are responsible for these associations, by what mechanisms they occur, and to what extent childhood cancer cases could be avoided by reducing or eliminating the phthalate content of medications and other consumer products.