Early-life exposure to PAE mixtures is associated with sex-specific alterations in reproductive hormone levels during minipuberty, highlighting minipuberty as a sensitive window for endocrine disruption and underscore the importance of considering chemical mixtures in environmental health research.
Abstract
Background Phthalates (PAEs) are ubiquitous endocrine-disrupting chemicals (EDCs) with well-documented prenatal effects, while their impact during early postnatal life remains less understood. Minipuberty, a transient activation of the hypothalamic-pituitary-gonadal (HPG) axis in early infancy, represents a critical window of endocrine programming. This study aimed to investigate the association between early-life exposure to PAEs and urinary reproductive hormone levels during minipuberty in healthy term-born infants. Methods This longitudinal study included infants from the Modena birth cohort with repeated urine sampling at birth (T0), 3 (T3), and 6 months (T6). Urinary concentrations of PAE metabolites (MMP, MEP, MnBP, MBzP, ΣDEHPm) and urine reproductive hormones (uLH, uFSH, uT and uE) were measured. Associations were assessed using sex-stratified Spearman correlations, single-pollutant linear regression models, and mixture approaches, including Weighted Quantile Sum (WQS) regression and quantile g-computation (qgcomp). Results PAE metabolites were evaluated in 162 infants and detected in nearly all samples, confirming widespread exposure. Consistent positive associations emerged between PAE exposure and urinary hormone levels. In males, increasing levels of metabolites were significantly associated particularly with increased uFSH and uT, at all timepoints. In females, associations were more evident at T3 and T6, mainly involving uFSH and uE. Mixture analyses confirmed these findings and identified MnBP, MBzP, and ΣDEHPm as the main contributors. Results were consistent across methods, highlighting a mixture association beside an isolated compound-specific findings. Conclusion Early-life exposure to PAE mixtures is associated with sex-specific alterations in reproductive hormone levels during minipuberty. These findings highlight minipuberty as a sensitive window for endocrine disruption and underscore the importance of considering chemical mixtures in environmental health research. However, further studies are needed to determine whether these early hormonal perturbations may have implications for long-term reproductive development and health.
Per- and polyfluoroalkyl substances (PFAS) are persistent endocrine-disrupting chemicals that readily cross the placenta and may interfere with hormonal systems essential for neurodevelopment and circadian regulation. We examined associations between prenatal exposure to individual PFAS and early childhood sleep quality. The analytic sample included 2,836 mother-child pairs from 14 study sites in the Environmental influences on Child Health Outcomes (ECHO) Cohort. We assessed Child Behavior Checklist (CBCL) Sleep Problems T-scores from ages 1-5 years. Maternal serum concentrations of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS) were measured during pregnancy. Linear mixed-effects models with random intercepts estimated associations between log2-transformed PFAS concentrations and CBCL scores, with covariate adjustment. The mean maternal age was 29.6 years, and the sample was racially and socioeconomically diverse (43% non-Hispanic White, 24% Black, and 23% Hispanic; 27% holding advanced degrees; and 36% reporting annual incomes <$30,000). In adjusted analyses, higher prenatal PFOA concentrations were associated with higher CBCL sleep problem scores in early childhood (β=0.13; 95% CI: 0.05, 0.21). Associations for PFOS, PFNA, and PFHxS were small and not statistically significant. Higher prenatal PFOA concentrations were associated with modestly higher CBCL Sleep Problems T-scores during early childhood, while associations for PFOS, PFNA, and PFHxS were small and imprecise. Although the magnitude of the observed PFOA association was modest, the findings add to a limited evidence base on prenatal PFAS exposure and parent-reported sleep-related behaviors in early childhood and warrant confirmation in future studies that incorporate harmonized trimester-specific exposure assessment, objective sleep measures, and mixture-based analytic approaches.
Cai Zhang, T. Etzel, S. Schantz et al.· Environmental Research· 0 citations
Abstract Introduction Some phthalates and their replacements are endocrine disrupting chemicals (EDCs) found in consumer products and linked to hypertensive disorders of pregnancy (HDP). Few studies have evaluated associations between EDCs and gestational blood pressure. Objective To evaluate associations between EDC biomarkers with gestational blood pressure. Methods The Environmental Reproductive and Glucose Outcomes study (N = 338) measured urinary concentrations of 18 phthalate and replacement metabolites and systolic (SBP) and diastolic (DBP) blood pressure at 3 pregnancy study visits (median: 12, 19, and 26 weeks’ gestation). Individual metabolite concentrations and summary measures based on common source or mechanism (eg, ΣPersonal care products [ΣPCP]) were log2-transformed, specific-gravity corrected, and modeled continuously and in quartiles. We estimated covariate-adjusted associations of individual metabolites and, summary measures with blood pressure using linear regression, and with HDP using log-binomial regression, assessing metabolite mixtures using Bayesian Kernel Machine Regression. Results HDP prevalence was 12.7%. Higher concentrations of monoethyl phthalate (MEP) and ΣPCP were most consistently associated with SBP and DBP elevations at visit 3. Higher concentrations of MEP (Q4 vs Q1) were associated with 4.59 mmHg higher SBP (95% CI: 0.04, 9.15), and higher ΣPCP (Q3 vs Q1) were associated with 5.78 mmHg (95% CI: 1.59, 9.97). Higher MEP and ΣPCP (Q4 vs Q1) were positively linked to DBP elevations of 4.51 to 4.70 mmHg. Other phthalate biomarkers were associated with blood pressure at specific time points. Discussion Certain urinary phthalate biomarkers, particularly MEP and ΣPCP, were associated with higher blood pressure levels in pregnancy, with implications for HDP.
K. Parra, Emma V. Preston, Marlee R. Quinn et al.· Journal of the Endocrine Soc...· 0 citations
The plasticizer butyl benzyl phthalate (BBP), a ubiquitous endocrine disruptor, is commonly used in PVC products and can leach into the environment, leading to human exposure. BBP has been detected in the placenta, amniotic fluid, and breast milk, indicating potential exposure during gestation and lactation. BBP is an endocrine disruptor compound (EDC) with estrogenic and anti-androgenic activity, which, at high or acute doses, may interfere with the development of hormone-dependent systems, including components of the neuro-immune-endocrine network (NIE) and sexual dimorphism. This study aimed to investigate the effects of perinatal BBP exposure on various components of the NIE network in adult male and female rats. Pregnant rats were administered drinking water with or without BBP (50 μg/L) from gestational day 5 until weaning. Offspring were assessed at 9 weeks of age by examining sex hormone levels in serum, immune cell populations in the spleen, neurotransmitters in the hippocampus, and cytokines in serum, hippocampus, and spleen. Results showed that BBP exposure led to lower weaning weights in both sexes, with persistent effects in males. Splenic T and T-helper lymphocyte populations increased in both sexes. In the hippocampus, females exhibited elevated proinflammatory cytokines, while males showed decreased serotonin levels, indicating sex-specific alterations in hormone, cytokine, and neurotransmitter levels in adult offspring.
D. L. Ruiz-Antonio, K. Nava-Castro, C. Garay-Canales et al.· Frontiers in Immunology· 0 citations
Prenatal TBEP exposure was associated with greater behavioral problems in early childhood, and Alter neonatal gut microbiota and related metabolic pathways may partly underlie this association.
Yuhan Zhou, Liyi Zhang, Qiang Li et al.· Environmental Research· 0 citations
Background: Prenatal exposure to the environmental toxicant methylmercury (MeHg) remains a significant public health concern, particularly during vulnerable developmental windows when toxicant susceptibility and sex-specific biology may shape long-term health outcomes. This study examined how a maternal diet spiked with environmentally relevant MeHg levels, including low (400 ppb) and high (800 ppb) concentrations reflecting federal and state consumption advisory guidelines for contaminated fish, affects fetal and postnatal growth, developmental maturation, and circulating biomarkers of liver function, inflammation, and oxidative stress in male and female offspring. Methods: Timed-pregnant Sprague-Dawley rats were exposed to diets containing vehicle, 400 ppb MeHg, or 800 ppb MeHg from gestational day (GD) 8 through late gestation (GD20) or parturition (GD22–23). Offspring were evaluated for fetal and placental growth (GD20), postnatal developmental milestones (eye opening and pubertal onset), postnatal growth trajectories, pubertal organ weights, and circulating biomarkers during puberty. Total Hg was quantified using direct thermal decomposition, gold amalgamation, and atomic absorption spectrometry. Plasma liver injury biomarkers and cytokine/chemokine profiles were measured using MILLIPLEZ magnetic bead assays. Circulating oxidized proteins were assessed using an advanced oxidation protein products (AOPP) assay. Results: Gestational MeHg exposure produced dose-dependent Hg accumulation in maternal, placental, fetal, and pubertal offspring tissues, with distinct sex differences in biodistribution. High dose MeHg exposure reduced placental weight but increased placental efficiency and delayed eye opening and male-but not female-pubertal onset. Postnatal growth effects were sex- and dose-dependent, with high dose MeHg-exposed males weighing less and high dose MeHg-exposed females weighing more during late adolescence. Organ weights and circulating biomarkers of liver function (ARG1, SDH, AST, 5’-NT) and inflammatory cytokines (TNF-α, IL-2, IL-1α, IL-17A, IL-6) in pubertal offspring were differentially altered by sex and MeHg dose, indicating persistent metabolic and immune dysregulation. Conclusions: Environmentally relevant prenatal MeHg exposure disrupts developmental trajectories and induces long-lasting, sex-specific alterations in growth, hepatic function, and inflammatory signaling. These findings highlight sex as a critical biological variable in developmental toxicology and underscore the need to consider sex-dependent mechanisms when evaluating early-life environmental exposures and their long-term health consequences.
Jessica L. Bradshaw, E. Wilson, Steve Mabry et al.· Research Square· 0 citations
Abstract Objectives Environmental endocrine disruptors (EDCs), particularly prevalent pesticide residues, are suspected contributors to the increasing incidence of central precocious puberty (CPP). This study explored the associations of urinary neonicotinoid insecticides (NNs) with sex hormones and pelvic ultrasound indicators in girls with CPP. Methods Girls were divided into three subgroups: CPP, non-CPP pubertal and prepubertal groups. Urinary levels of nine pesticides were screened via Kruskal-Wallis H test with Dunn’s test; only nitenpyram (NIT) with intergroup differences was further analyzed. Stratified correlation and adjusted linear regression assessed links between NIT and sexual development markers, while quartile-based logistic regression examined the dose–response association between NIT and CPP risk. Results Thiamethoxam (THI), clothianidin (CLO), flupyradifurone (FPF), and sulfoxaflor (SUL) showed a 100 % detection rate, while thiacloprid (THIA) was the least detected (85.8 %). The NIT concentration was significantly higher in the CPP group (p<0.05). Stratified multivariate linear regression adjusted for age and BMI-SDS demonstrated that elevated NIT was independently positively associated with ovarian volume (OV) (B=0.73, 95 % CI: 0.15–1.31, p=0.014, β=0.294) and estradiol (E2) (B=116.64, 95 % CI: 49.58–183.70, p=0.002, β=0.682) only in CPP group, while no significant correlations were detected in non-CPP pubertal or prepubertal groups. Logistic regression revealed a significant ascending dose–response trend between elevated NIT quartiles and CPP risk (p for trend=0.048). Conclusions NIT exposure acts as an independent environmental risk factor for CPP in girls, and aggravates sex hormone disturbance and abnormal ovarian development only in children with CPP. Restricting daily children’s exposure to NNs is clinically and public health meaningful.
Pingping Wang, Xuefeng Jin, Suhong Yang et al.· Journal of Pediatric Endocri...· 0 citations