The role of the aryl hydrocarbon receptor in mediating the effects of mono(2-ethylhexyl) phthalate in mouse ovarian antral follicles†.

Di(2-ethylhexyl) phthalate (DEHP) is a pervasive environmental toxicant used in the manufacturing of numerous consumer products, medical supplies, and building materials. DEHP is metabolized to mono(2-ethylhexyl) phthalate (MEHP). MEHP is an endocrine disruptor that adversely affects folliculogenesis and steroidogenesis in the ovary, but its mechanism of action is not fully understood. Thus, we tested the hypothesis that the aryl hydrocarbon receptor (AHR) plays a functional role in MEHP-mediated disruption of folliculogenesis and steroidogenesis. CD-1 mouse antral follicles were isolated and cultured with MEHP (0-400 µM) in the presence or absence of the AHR antagonist CH223191 (1 µM). MEHP treatment reduced follicle growth over a 96-h period, and this effect was partially rescued by co-culture with CH223191. MEHP exposure alone increased expression of known AHR targets, cytochrome P450 (CYP) enzymes Cyp1a1 and Cyp1b1, and this induction was blocked by CH223191. MEHP reduced media concentrations of estrone and estradiol compared to control. This effect was mitigated by co-culture with CH223191. Moreover, MEHP reduced the expression of the estrogen-sensitive genes progesterone receptor (Pgr) and luteinizing hormone/choriogonadotropin receptor (Lhcgr) and co-treatment with CH223191 blocked this effect. Collectively, these data indicate that MEHP activates the AHR to impair follicle growth and reduce estrogen production and signaling in ovarian antral follicles.

The effects of short-term and long-term phthalate exposures on ovarian follicle growth dynamics and hormone levels in female mice†.

Di(2-ethylhexyl) phthalate and diisononyl phthalate are widely used as plasticizers in polyvinyl chloride products. Short-term exposures to phthalates affect hormone levels, ovarian follicle populations, and ovarian gene expression. However, limited data exist regarding the effects of long-term exposure to phthalates on reproductive functions. Thus, this study tested the hypothesis that short-term and long-term exposure to di(2-ethylhexyl) phthalate or diisononyl phthalate disrupts follicle dynamics, ovarian and pituitary gene expression, and hormone levels in female mice. Adult CD-1 female mice were exposed to vehicle, di(2-ethylhexyl) phthalate, or diisononyl phthalate (0.15 ppm, 1.5 ppm, or 1500 ppm) via the chow for 1 or 6 months. Short-term exposure to di(2-ethylhexyl) phthalate (0.15 ppm) and diisononyl phthalate (1.5 ppm) decreased serum follicle-stimulating hormone levels compared to control. Long-term exposure to di(2-ethylhexyl) phthalate and diisononyl phthalate (1500 ppm) increased the percentage of primordial follicles and decreased the percentages of preantral and antral follicles compared to control. Both phthalates increased follicle-stimulating hormone levels (di(2-ethylhexyl) phthalate at 1500 ppm; diisononyl phthalate at 1.5 ppm) and decreased luteinizing hormone levels (di(2-ethylhexyl) phthalate at 0.15 and 1.5 ppm; diisononyl phthalate at 1.5 ppm and 1500 ppm) compared to control. Furthermore, both phthalates altered the expression of pituitary gonadotropin subunit genes (Cga, Fshb, and Lhb) and a transcription factor (Nr5a1) that regulates gonadotropin synthesis. These data indicate that long-term exposure to di(2-ethylhexyl) phthalate and diisononyl phthalate alters follicle growth dynamics in the ovary and the expression of gonadotropin subunit genes in the pituitary and consequently luteinizing hormone and follicle-stimulating hormone synthesis.

Endocrine disruption and male reproductive disorders: unanswered questions.

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

Long-term exposure to the mixture of phthalates induced male reproductive toxicity in rats and the alleviative effects of quercetin.

Phthalates (PEs), such as di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and butyl benzyl phthalate (BBP) could cause reproductive and developmental toxicities, while human beings are increasingly exposed to them at low-doses. Phytochemical quercetin (Que) is a flavonoid that has estrogenic effect, anti-inflammatory and anti-oxidant effects. This study was conducted to assess the alleviative effect of Que. on male reproductive toxicity induced by the mixture of three commonly used PEs (MPEs) at low-dose in rats, and explore the underlying mechanism. Male rats were treated with MPEs (16 mg/kg/day) and/or Que. (50 mg/kg/d) for 91 days. The results showed that MPEs exposure caused male reproductive injuries, such as decreased serum sex hormones levels, abnormal testicular pathological structure, increased abnormal sperm rate and changed expressions of PIWIL1 and PIWIL2. Furthermore, MPEs also changed the expression of steroidogenic proteins in steroid hormone metabolism, including StAR, CYP11A1, CYP17A1, 17ß-HSD, CYP19A1. However, the alterations of these parameters were reversed by Que. MPEs caused male reproductive injuries in rats; Que. inhibited MPEs' male reproductive toxicity, which might relate to the improvement of testosterone biosynthesis.

Association between Biomarkers of Phthalate Exposure and Serum Folate Concentrations in Children: A Population-Based Cross-Sectional Study of the NHANES from 2011 to 2016.

BACKGROUND: Although adverse health effects of phthalates have been reported, very few studies have assessed the associations between biomarkers of phthalate exposure and serum folate concentrations in children. OBJECTIVES: We aimed to examine the association between urinary phthalate metabolites, as biomarkers of exposure to phthalates, and total serum folate concentrations in children using national data from the United States. METHODS: We conducted cross-sectional analyses of 2100 individuals aged 6-18 y enrolled in the National Health and Nutrition Examination Survey, 2011-2016. Multivariable linear regression was applied to examine the relationship between natural logarithm (ln)-transformed urinary phthalate metabolites and serum folate concentrations. The quantile-based g-computation was used to assess the association of urinary phthalate metabolite mixture with serum folate levels. Subgroup analyses were conducted by sex, age, and race/ethnicity, and the interactions were assessed by adding interaction terms of these stratifying variables and phthalates and modeling through the Wald test. RESULTS: In multiple linear regression models, for participants in the highest tertile of MEHHP, MEOHP, DEHP, MCPP, and MCOP, total serum folate concentrations were 1.566 [ß: -1.566; 95% confidence interval: -2.935, -0.196], 1.423 (-1.423; -2.689, -0.157), 1.309 (-1.309; -2.573, -0.044), 1.530 (-1.530; -2.918, -0.142), and 1.381 (-1.381; -2.641, -0.122) ng/mL lower than those in the lowest tertile. The inverse associations were consistent in different subgroups by sex, age, and race/ethnicity (P for interaction ≥0.083 for all). In addition, the phthalate mixture showed a strong inverse correlation with serum folate; a quartile increase in the phthalate mixture on the ln scale was associated with 0.888 (-0.888; -1.677, -0.099) ng/mL decrease in the serum folate. CONCLUSIONS: Higher concentrations of urinary phthalate metabolites were associated with lower serum folate concentrations in children. Although our findings should be validated through additional population and mechanistic studies, they support a potential adverse effect of phthalate exposure on folate metabolism in children.

Placental Transcriptomic Signatures of Prenatal Phthalate Exposure and Identification of Placenta-Brain Genes Associated with the Effects of Phthalate Exposure on Neurodevelopment in Children.

Prenatal exposure to phthalates may affect placental function and fetal development, but the underlying mechanisms are unclear. The aim of our study was to explore the alterations in the placental transcriptome associated with prenatal phthalate exposure and to further analyze whether the placental-brain axis (PBA) genes play a mediating role in the association between prenatal phthalate exposure and children's neurodevelopment. We included 172 participants from the Ma'anshan Birth Cohort and collected data on seven phthalate metabolites in urine during pregnancy, placental tissue RNA-seq, and neurodevelopment of offspring. Bioinformatics analysis revealed that aberrant regulation of the placental transcriptome was associated with prenatal phthalate exposure. Exposure to phthalates during pregnancy was found to be associated with neurodevelopmental delay in children aged 6, 18, and 48 months using the multiple linear regression model. Meanwhile, employing mediation analysis, nine PBA genes were identified that mediate the association between exposure to phthalates during pregnancy and the neurodevelopment of children. Our study will provide a basis for potential mechanisms by which prenatal exposure to phthalates affects placental function and children's neurodevelopment.

A Noninvasive Quantitative Method for Evaluating Intestinal Exposure to Microplastics Based on the Excretion and Metabolism Patterns of Microplastics and Their Additives.

Microplastics (MPs) pose potential health risks to the intestinal tract and gut microbiota, a topic that has garnered significant attention. However, the absence of quantitative assessment methods for human gut MP exposure impedes related health risk assessments. Here, we performed long-term continuous exposure experiments on mice using MPs that mimic actual human exposure characteristics. The daily excretion of fecal MPs and the concentrations of phthalates (PAEs) and their metabolites (mPAEs) in serum and urine were detected. The cumulative excretion rate of fecal MPs remains stable at about 93%. A significant linear correlation was observed between MP exposure and concentration of mPAEs in urine for both low MP (LMP; 150 µg of MPs/d) (R2 = 0.90) and high MP (HMP; 360 µg of MPs/d) groups (R2 = 0.97). Moreover, a strong correlation was found between daily PAEs exposure and total MP-associated PAEs exposure in both LMP (R2 = 0.77) and HMP (R2 = 0.88) groups. Based on these findings, we established a noninvasive model and evaluated multiple MP exposure parameters in the human gut across 6 continents, 30 countries, and 133 individuals. This study offers novel insights for the quantitative assessment of in vivo MP exposure and provides technical support for assessing the health risks of MPs.

Metabolomic Alterations Associated with Phthalate Exposures among Pregnant Women in Puerto Rico.

Although phthalate exposure has been linked with multiple adverse pregnancy outcomes, their underlying biological mechanisms are not fully understood. We examined associations between biomarkers of phthalate exposures and metabolic alterations using untargeted metabolomics in 99 pregnant women and 86 newborns [mean (SD) gestational age = 39.5 (1.5) weeks] in the PROTECT cohort. Maternal urinary phthalate metabolites were quantified using isotope dilution high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS), while metabolic profiles in maternal and cord blood plasma were characterized via reversed-phase LC-MS. Multivariable linear regression was used in metabolome-wide association studies (MWAS) to identify individual metabolic features associated with elevated phthalate levels, while clustering and correlation network analyses were used to discern the interconnectedness of biologically relevant features. In the MWAS adjusted for maternal age and prepregnancy BMI, we observed significant associations between specific phthalates, namely, di(2-ethylhexyl) phthalate (DEHP) and mono(3-carboxypropyl) phthalate (MCPP), and 34 maternal plasma metabolic features. These associations predominantly included upregulation of fatty acids, amino acids, purines, or their derivatives and downregulation of ceramides and sphingomyelins. In contrast, fewer significant associations were observed with metabolic features in cord blood. Correlation network analysis highlighted the overlap of features associated with phthalates and those identified as differentiating markers for preterm birth in a previous study. Overall, our findings underscore the complex impact of phthalate exposures on maternal and fetal metabolism, highlighting metabolomics as a tool for understanding associated biological processes. Future research should focus on expanding the sample size, exploring the effects of phthalate mixtures, and validating identified metabolic features in larger, more diverse populations.

Serum Phthalate Concentrations and Biomarkers of Oxidative Stress in Adipose Tissue in a Spanish Adult Cohort.

The relationship between phthalates, a group of chemical pollutants classified as endocrine disruptors, and oxidative stress is not fully understood. The aim of the present hospital-based study was to explore the associations between circulating levels of 10 phthalate metabolites and 8 biomarkers of oxidative stress in adipose tissue. The study population (n = 143) was recruited in two hospitals in the province of Granada (Spain). Phthalate metabolite concentrations were analyzed by isotope diluted online-TurboFlow-LC-MS/MS in serum samples, while oxidative stress markers were measured by commercially available kits in adipose tissue collected during routine surgery. Statistical analyses were performed by MM estimators' robust linear regression and weighted quantile sum regression. Mainly, positive associations were observed of monomethyl phthalate (MMP), monoiso-butyl phthalate (MiBP), and mono-n-butyl phthalate (MnBP) (all low molecular weight phthalates) with glutathione peroxidase (GPx) and thiobarbituric acid reactive substances (TBARS), while an inverse association was found between monoiso-nonyl phthalate (MiNP) (high molecular weight phthalate) and the same biomarkers. WQS analyses showed significant effects of the phthalate mixture on GSH (ß = -30.089; p-value = 0.025) and GSSG levels (ß = -19.591; p-value = 0.030). Despite the limitations inherent to the cross-sectional design, our novel study underlines the potential influence of phthalate exposure on redox homeostasis, which warrants confirmation in further research.

Exposure to Phthalates and Alternative Plasticizers in Patients with Impaired Kidney Function in Korea: Temporal Trend during 2011-2020 and Its Association with Chronic Kidney Disease.

Phthalates are chemical risk factors of chronic kidney disease (CKD); however, little is known about temporal trends of phthalate exposure and associated health risks among CKD patients. Such information is even scarce for alternative plasticizers. CKD patients were recruited from 2011 to 2020 in Korea (n = 200) and assessed for the temporal changes of both traditional and alternative plasticizer exposure. Their associations with kidney dysfunction were also investigated. In CKD patients, urinary levels of DEP, BBzP, and DEHP metabolites declined significantly during this period, while those of the DEHTP metabolite increased. The level of DEHP metabolites showed a negative association with the estimated glomerular filtration rate (eGFR) in multiple association models, but additional eGFR subgroup analysis failed to show consistent results. Associations between phthalate exposure and eGFR were influenced by the severity of kidney dysfunction: DEHP and BBzP exposure showed negative associations with eGFR only among the patients with moderate kidney dysfunction (eGFR 30-59 mL/min/1.73 m2). Changing associations by CKD severity may be explained by negative correlations between eGFR and both urinary creatinine concentration and specific gravity. Our observations show that DEHTP has rapidly replaced DEHP and exposure to several phthalates adversely influences kidney function even among CKD patients.

Personal Care Products, Socioeconomic Status, and Endocrine-Disrupting Chemical Mixtures in Black Women.

Personal care products (PCPs) are sources of exposure to endocrine-disrupting chemicals (EDCs) among women, and socioeconomic status (SES) may influence these exposures. Black women have inequitable exposure to EDCs from PCP use, but no study has investigated how exposure to EDCs through PCPs may vary by SES, independent of race. Using data from the Study of Environment, Lifestyle, and Fibroids, a cohort of reproductive-aged Black women (n = 751), we quantified associations between PCPs and urinary biomarker concentrations of EDC mixtures (i.e., phthalates, phenols, parabens) within SES groups, defined using k-modes clustering based on education, income, marital status, and employment. Information about PCP use and SES was collected through questionnaires and interviews. We used principal component analysis to characterize the EDC mixture profiles. Stratified linear regression models were fit to assess associations between PCP use and EDC mixture profiles, quantified as mean differences in PC scores, by SES group. Associations between PCP use and EDC mixture profiles varied by SES group; e.g., vaginal powder use was associated with a mixture of phenols among lower SES women, whereas this association was null for higher SES women. Findings suggest that SES influences PCP EDC exposure in Black women, which has implications for public health interventions.

Phthalates Boost Natural Transformation of Extracellular Antibiotic Resistance Genes through Enhancing Bacterial Motility and DNA Environmental Persistence.

The environmental dissemination of extracellular antibiotic resistance genes (eARGs) in wastewater and natural water bodies has aroused growing ecological concerns. The coexisting chemical pollutants in water are known to markedly affect the eARGs transfer behaviors of the environmental microbial community, but the detailed interactions and specific impacts remain elusive so far. Here, we revealed a concentration-dependent impact of dimethyl phthalate (DMP) and several other types of phthalate esters (common water pollutants released from plastics) on the natural transformation of eARGs. The DMP exposure at an environmentally relevant concentration (10 µg/L) resulted in a 4.8-times raised transformation frequency of Acinetobacter baylyi but severely suppressed the transformation at a high concentration (1000 µg/L). The promotion by low-concentration DMP was attributed to multiple mechanisms, including increased bacterial mobility and membrane permeability to facilitate eARGs uptake and improved resistance of the DMP-bounded eARGs (via noncovalent interaction) to enzymatic degradation (with suppressed DNase activity). Similar promoting effects of DMP on the eARGs transformation were also found in real wastewater and biofilm systems. In contrast, higher-concentration DMP suppressed the eARGs transformation by disrupting the DNA structure. Our findings highlight a potentially underestimated eARGs spreading in aquatic environments due to the impacts of coexisting chemical pollutants and deepen our understanding of the risks of biological-chemical combined pollution in wastewater and environmental water bodies.

Legacy and Emerging Plasticizers and Stabilizers in PVC Floorings and Implications for Recycling.

Hazardous chemicals in building and construction plastics can lead to health risks due to indoor exposure and may contaminate recycled materials. We systematically sampled new polyvinyl chloride floorings on the Swiss market (n = 151). We performed elemental analysis by X-ray fluorescence, targeted and suspect gas chromatography-mass spectrometry analysis of ortho-phthalates and alternative plasticizers, and bioassay tests for cytotoxicity and oxidative stress, and endocrine, mutagenic, and genotoxic activities (for selected samples). Surprisingly, 16% of the samples contained regulated chemicals above 0.1 wt %, mainly lead and bis(2-ethylhexyl) phthalate (DEHP). Their presence is likely related to the use of recycled PVC in new flooring, highlighting that uncontrolled recycling can delay the phase-out of hazardous chemicals. Besides DEHP, 29% of the samples contained other ortho-phthalates (mainly diisononyl and diisodecyl phthalates, DiNP and DiDP) above 0.1 wt %, and 17% of the samples indicated a potential to cause biological effects. Considering some overlap between these groups, they together make up an additional 35% of the samples of potential concern. Moreover, both suspect screening and bioassay results indicate the presence of additional potentially hazardous substances. Overall, our study highlights the urgent need to accelerate the phase-out of hazardous substances, increase the transparency of chemical compositions in plastics to protect human and ecosystem health, and enable the transition to a safe and sustainable circular economy.

Association between phthalates exposure and myocardial damage in the general population: A cross-sectional study.

BACKGROUND: Cardiovascular consequences of phthalates exposure have been given increasing attention, but the association of phthalates with subclinical cardiovascular disease (CVD) was unknown. Accordingly, this study aimed to investigate the association between phthalates exposure and high-sensitivity cardiac troponin I (hs-cTnI), a marker of myocardial injury, which was detectable in the subclinical stage of CVD. METHODS: Participants aged 6 years or older with available urinary phthalates metabolites and serum hs-cTnI concentrations were included in the National Health and Nutrition Examination Survey 2003-2004 cycle. Multivariable linear regression and weighted quantiles sum (WQS) regression were used to assess the association of hs-cTnI with individual phthalates and their co-exposure. Di-2-ethylhexylphthalate (ΣDEHP), high-molecular-weight phthalate (ΣHMWP), and low-molecular-weight phthalate (ΣLMWP) were defined as the molecular sum of phthalates metabolites in urine. RESULTS: 2241 participants were finally included. The percent change of serum hs-cTnI concentrations related to per 1-standard deviation increase of logarithmic urinary phthalates concentrations was 3.4% (0.1-6.7, P = 0.04) for ΣDEHP, 3.6% (0.3-6.9, P = 0.03) for ΣHMWP, and 3.5% (0.2-6.8, P = 0.04) for ΣLMWP. Co-exposure to phthalates metabolites expressed as the WQS index also demonstrated a positive association with hs-cTnI. A similar association pattern was found in the population with no prior CVD. CONCLUSIONS: This study indicated the potential of phthalates to myocardial injury which may occur even before clinically apparent CVD was identified, emphasizing the significance of reducing phthalates in the prevention of CVD.

Urinary metabolite concentrations of phthalate and plasticizers in infancy and childhood in the UNC baby connectome project.

INTRODUCTION: Existing evidence suggests that exposure to phthalates is higher among younger age groups. However, limited knowledge exists on how phthalate exposure, as well as exposure to replacement plasticizers, di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) and di-2-ethylhexyl terephthalate (DEHTP), change from infancy through early childhood. METHODS: Urine samples were collected across the first 5 years of life from typically developing infants and young children enrolled between 2017 and 2020 in the longitudinal UNC Baby Connectome Project. From 438 urine samples among 187 participants, we quantified concentrations of monobutyl phthalate (MnBP), mono-3-carboxypropyl phthalate (MCPP), monoisobutyl phthalate (MiBP), monoethyl phthalate (MEP), monobenzyl phthalate (MBzP), and metabolites of di(2-ethylhexyl) phthalate (DEHP), diisonoyl phthalate (DiNP), DINCH and DEHTP. Specific gravity (SG) adjusted metabolite and molar sum concentrations were compared across age groups. Intraclass correlation coefficients (ICCs) were calculated among 122 participants with multiple urine specimens (373 samples). RESULTS: Most phthalate metabolites showed high detection frequencies (>80% of samples). Replacement plasticizers DINCH (58-60%) and DEHTP (>97%) were also commonly found. DiNP metabolites were less frequently detected (<10%). For some metabolites, SG-adjusted concentrations were inversely associated with age, with the highest concentrations found in the first year of life. ICCs revealed low to moderate reliability in metabolite measurements (ρ = 0.10-0.48) suggesting a high degree of within-individual variation in exposure among this age group. The first 6 months (compared to remaining age groups) showed an increased ratio of carboxylated metabolites of DEHP and DEHTP, compared to other common metabolites, but no clear age trends for DINCH metabolite ratios were observed. CONCLUSION: Metabolites of phthalates and replacements plasticizers were widely detected in infancy and early childhood, with the highest concentrations observed in the first year of life for several metabolites. Higher proportions of carboxylated metabolites of DEHP and DEHTP in younger age groups indicate potential differences in metabolism during infancy.

Association of phthalate exposure with reproductive outcomes among infertile couples undergoing in vitro fertilization: A systematic review.

Human fertility is impacted by changes in lifestyle and environmental deterioration. To increase human fertility, assisted reproductive technology (ART) has been extensively used around the globe. As early as 2009, the Endocrine Society released its first scientific statement on the potential adverse effects of environmental endocrine-disrupting chemicals (EDCs) on human health and disease development. Chemicals known as phthalates, frequently employed as plasticizers and additives, are common EDCs. Numerous studies have shown that phthalate metabolites in vivo exert estrogen-like or anti-androgenic effects in both humans and animals. They are associated with the progression of a range of diseases, most notably interference with the reproductive process, damage to the placenta, and the initiation of chronic diseases in adulthood. Phthalates are ingested by infertile couples in a variety of ways, including household products, diet, medical treatment, etc. Exposure to phthalates may exacerbate their infertility or poor ART outcomes, however, the available data on phthalate exposure and ART pregnancy outcomes are sparse and contradictory. Therefore, this review conducted a systematic evaluation of 16 papers related to phthalate exposure and ART pregnancy outcomes, to provide more aggregated results, and deepen our understanding of reproductive outcomes in infertile populations with phthalate exposure.

Exposure to endocrine-disrupting plasticisers and lung function in children and adolescents: A systematic review and meta-analysis.

Exposure to endocrine-disrupting plasticisers (EDPs), such as phthalates and bisphenols, has been associated with reduced lung function in children and adolescents. However, the existing literature yields conflicting results. This systematic review and meta-analysis aimed to assess the epidemiologic evidence investigating the association between EDP exposure and lung function in children and adolescents. A comprehensive search of five databases identified 25 relevant studies. We employed a random-effects meta-analysis on spirometry measures. The effect size of interest was the change in lung function in standard deviation (SD) units resulting from a two-fold increase in exposure levels. We found that certain phthalates marginally reduced lung function in children. Forced expiratory volume in 1 s (FEV1) was reduced by a two-fold increase in mono-benzyl phthalate (MBzP) (ß = -0.025 SD, 95%CI: 0.042, -0.008), mono-ethyl-oxo-hexyl phthalate (MEOHP) (ß = -0.035 SD, 95%CI: 0.057, -0.014) and mono-carboxy-nonyl phthalate (MCNP) (ß = -0.024 SD, 95%CI: 0.05, -0.003). Forced vital capacity (FVC) was decreased by a two-fold increase in MBzP (ß = -0.022 SD, 95%CI: 0.036, -0.008) and MEOHP (ß = -0.035 SD, 95%CI: 0.057, -0.014) levels. A two-fold increase in MCNP levels was associated with lower FEV1/FVC (ß = -0.023 SD, 95%CI: 0.045, -0.001). Furthermore, a two-fold increase in MEOHP levels reduced forced mid-expiratory flow (FEF25-75) (ß = -0.030 SD, 95%CI: 0.055, -0.005) and peak expiratory flow (PEF) (ß = -0.056 SD, 95%CI: 0.098, -0.014). Notably, associations were more pronounced in males. Given the potential for reverse causation bias, the association between childhood exposure to EDPs and lung function remains uncertain. Overall, our meta-analysis showed small reductions in lung function with higher phthalate exposure. However, future studies are warranted in younger age groups.

Phthalate and DINCH metabolites in the urine of Hungarian schoolchildren: Cumulative risk assessment and exposure determinants.

A human biomonitoring study was conducted to assess the exposure of Hungarian children aged 8-11 years to ten phthalate esters (PEs) and DINCH between 2017 and 2018. In addition to collecting urine samples from 262 participants, a questionnaire was completed by the parents or legal guardians to identify potential determinants of exposure. The highest geometric mean concentration was observed for MiBP, followed by MBP, cx- MEHP, OH-MEHP and MEP. Three out of the four DINCH metabolites were detected in more than 90% of the samples. The comparison of the urinary concentrations measured in this study with those observed in the DEMOCOPHES study revealed a significant decreasing trend in all PE metabolites investigated in both studies between 2011/2012 and 2017/2018. Different approaches were used to assess the health risks associated with the exposure to PEs and DINCH. Our results highlighted that the hazard index (HI) values were higher than 1 in 17.6% of the children when the human biomonitoring guidance values were applied. In contrast, less than 3% of the children had HI values exceeding 1 when other sources of reference values were used. By applying a safety factor of 10 for the risk assessment, 17.6-91.6% of the children were characterized by HI values higher than 0.1, indicating the need for risk reduction measures. Overall, DnBP, DiBP and DEHP were identified as the main drivers of the mixture risk. Although PEs and DINCH are ubiquitous contaminants, there are still inconsistencies and gaps in our understanding of the determinants of exposure. The results of the multivariate regression analysis showed significant associations between PE or DINCH metabolite concentrations and certain individual characteristics, use of personal care products, home and school environment and food and beverages consumption 24 h prior to sample collection.

Developmental exposure to environmentally relevant doses of phthalates alters the neural control of male and female reproduction in mice.

The present study aims to analyze the effects of developmental exposure to phthalates at environmentally relevant doses on the neural control of male and female reproduction. For this purpose, C57Bl/6J mice were exposed to di-(2-ethylexyl) phthalate (DEHP) alone (5 or 50 µg/kg/d), or DEHP (5 µg/kg/d) in a phthalate mixture. Exposure through diet started 6 weeks before the first mating and lasted until weaning of litters from the second gestation (multiparous dams). Analyses of offspring born from multiparous dams exposed to DEHP alone or in a phthalate mixture showed that females experienced a delayed pubertal onset, and as adults they had prolonged estrous cyclicity and reduced Kiss1 expression in the preoptic area and mediobasal hypothalamus. Male littermates showed a reduced anogenital distance and delayed pubertal onset compared with controls. However, in adulthood the weight of androgen-sensitive organs and hypothalamic Kiss1 expression were unaffected, suggesting normal functioning of the male gonadotropic axis. Developmental exposure to DEHP alone or in a phthalate mixture reduced the ability of intact males and ovariectomized and hormonally primed females to attract a sexual partner and to express copulatory behaviors. In addition, females were unable to discriminate between male and female stimuli in the olfactory preference test. Social interaction was also impaired in females, while locomotor activity and anxiety-like behavior in both sexes were unaffected by the treatment. The sexual deficiencies were associated with reduced expression of the androgen receptor in the preoptic area and progesterone receptor in the mediobasal hypothalamus, the key regions involved in male and female sexual behavior, respectively. Thus, the neural structures controlling reproduction are vulnerable to developmental exposure to phthalates at environmentally relevant doses in male and female mice. Adult females had an impaired gonadotropic axis and showed more affected behaviors than adult males.

Trimester-specific effect of maternal co-exposure to organophosphate esters and phthalates on preschooler cognitive development: The moderating role of gestational vitamin D status.

Organophosphate esters (OPEs) and phthalate acid esters (PAEs) are prevalent endocrine-disrupting chemicals (EDCs). Humans are often exposed to OPEs and PAEs simultaneously through multiple routes. Given that fetal stage is a critical period for neurodevelopment, it is necessary to know whether gestational co-exposure to OPEs and PAEs affects fetal neurodevelopment. However, accessible epidemiological studies are limited. The present study included 2, 120 pregnant women from the Ma'anshan Birth Cohort (MABC) study. The concentrations of tris (2-chloroethyl) phosphate (TCEP), 6 OPE metabolites and 7 PAE metabolites were measured in the first, second and third trimester using ultra-performance liquid chromatography-tandem mass spectrometry (LC-MS). Cognitive development of preschooler was assessed based on the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition (WPPSI-IV) of the Chinese version. Generalized estimating equations (GEEs), restricted cubic spline (RCS) and generalized additive models (GAMs) were employed to explore the associations between individual OPE exposure and preschooler cognitive development. The quantile-based g-computation (QGC) method was used to estimate the joint effect of PAEs and OPEs exposure on cognitive development. GEEs revealed significant adverse associations between diphenyl phosphate (DPHP) (ß: -0.58, 95% CI: -1.14, -0.01), bis (2-butoxyethyl) phosphate(BBOEP) (ß: -0.44, 95% CI: -0.85, -0.02), bis(1-chloro-2-propyl) phosphate (BCIPP) (ß: -0.81, 95%CI: -1.43, -0.20) and full-scale intelligence quotient (FSIQ) in the first trimester; additionally, TCEP and bis(2-ethylhexyl) phosphate (BEHP) in the second trimester, as well as DPHP in the third trimester, were negatively associated with cognitive development. Through the QGC analyses, mixture exposure in the first trimester was negatively associated with FSIQ scores (ß: -1.70, 95% CI: -3.06, -0.34), mono-butyl phthalate (MBP), BCIPP, and DPHP might be the dominant contributors after controlling for other OPEs and PAEs congeners. Additionally, the effect of OPEs and PAEs mixture on cognitive development might be driven by vitamin D deficiency.