Sex-Specific and Trimester-Specific Associations of Prenatal Exposure to Bisphenols, Parabens, and Triclosan with Neonatal Birth Size and Gestational Age.

Bisphenols, parabens, and triclosan (TCS) are common endocrine disrupters used in various consumer products. These chemicals have been shown to cross the placental barrier and affect intrauterine development of fetuses. In this study, we quantified serum levels of six bisphenols, five parabens, and TCS in 483 pregnant women from southern China. Quantile-based g-computation showed that combined exposure to bisphenols, parabens, and TCS was significantly (p < 0.05) and negatively associated with birth weight (ß = -39.9, 95% CI: -73.8, -6.1), birth length (ß = -0.19, 95% CI: -0.34, -0.04), head circumference (ß = -0.13, 95% CI: -0.24, -0.02), and thoracic circumference (ß = -0.16, 95% CI: -0.29, -0.04). An inverse correlation was also identified between mixture exposure and gestational age (ß = -0.12, 95% CI: -0.24, -0.01). Bisphenol A (BPA), bisphenol Z (BPZ), bisphenol AP (BPAP), propylparaben (PrP), and TCS served as the dominant contributors to the overall effect. In subgroup analyses, male newborns were more susceptible to mixture exposure than females, whereas the exposure-outcome link was prominent among pregnant women in the first and second trimesters. More evidence is warranted to elucidate the impacts of exposure to mixtures on birth outcomes, as well as the underlying mechanisms.

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.

New analytical method for the determination of endocrine disruptors in human faeces using gas chromatography coupled to tandem mass spectrometry.

Endocrine-disrupting chemicals are environmental pollutants that can enter our bodies and cause diverse pathologies. Some bisphenols and parabens have been shown to be capable of modifying proper functioning of the endocrine system. Among other dysfunctions, endocrine-disrupting chemicals can cause changes in intestinal microbiota. Faeces are a convenient matrix that can be useful for identifying the quantity of endocrine disruptors that reach the intestine and the extent to which the organism is exposed to these pollutants. The present work developed a new analytical method to determine 17 compounds belonging to the paraben and bisphenol families found in human faeces. The extraction method was optimized using an ultrasound-assisted extraction technique followed by a clean-up step based on the QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) technique. Optimization was performed using the design of experiments technique. In validation analysis, the method was proven to be linear over a wide range. R-squared outcomes were between 95 and 99%. Selectiveness and sensitivity outcomes were acceptable, with detection limits being between 1 and 10 ng g-1 in all cases, whilst quantification limits were between 3 and 25 ng g-1 in all instances, with the exception of bisphenol AF. The method was deemed accurate, with recovery values being close to 100% and relative standard deviations being lower than 15% in all cases. Applicability was examined by analysing 13 samples collected from volunteers (male and female). All samples were contaminated with at least one of the analytes studied. The most commonly found compounds were methylparaben and bisphenol A, which were detected in almost all samples and quantitatively determined in 11 and 12 samples, respectively. Of the 17 compounds analysed, 11 were found in at least one sample. Outcomes demonstrate that faeces can be a good matrix for the determination of exposure to contaminants of interest here.

Environmental phenol exposures in 6- to 12-week-old infants: The Infant Feeding and Early Development (IFED) study.

BACKGROUND: Exposure to phenols, endocrine-disrupting chemicals used in personal care and consumer products, is widespread. Data on infant exposures are limited despite heightened sensitivity to endocrine disruption during this developmental period. We aimed to describe distributions and predictors of urinary phenol concentrations among U.S. infants ages 6-12 weeks. METHODS: The Infant Feeding and Early Development (IFED) study is a prospective cohort study of healthy term infants enrolled during 2010-2013 in the Philadelphia region. We measured concentrations of seven phenols in 352 urine samples collected during the 6- or 8- and/or 12-week study visits from 199 infants. We used linear mixed models to estimate associations of maternal, sociodemographic, infant, and sample characteristics with natural-log transformed, creatinine-standardized phenol concentrations and present results as mean percent change from the reference level. RESULTS: Median concentrations (µg/L) were 311 for methylparaben, 10.3 for propylparaben, 3.6 for benzophenone-3, 2.1 for triclosan, 1.0 for 2,5-dichlorophenol, 0.7 for BPA, and 0.3 for 2,4-dichlorophenol. Geometric mean methylparaben concentrations were approximately 10 times higher than published estimates for U.S. children ages 3-5 and 6-11 years, while propylparaben concentrations were 3-4 times higher. Infants of Black mothers had higher concentrations of BPA (83%), methylparaben (121%), propylparaben (218%), and 2,5-dichorophenol (287%) and lower concentrations of benzophenone-3 (-77%) and triclosan (-53%) than infants of White mothers. Triclosan concentrations were higher in breastfed infants (176%) and lower in infants whose mothers had a high school education or less (-62%). Phenol concentrations were generally higher in summer samples. CONCLUSIONS: Widespread exposure to select environmental phenols among this cohort of healthy U.S. infants, including much higher paraben concentrations compared to those reported for U.S. children, supports the importance of expanding population-based biomonitoring programs to infants and toddlers. Future investigation of exposure sources is warranted to identify opportunities to minimize exposures during these sensitive periods of development.

Human exposure to methyl and butyl parabens and their transformation products in settled dust collected from urban, semi-urban, rural, and tribal settlements in a tropical environment.

The present study involved monitoring the distribution of two widely consumed parabens (methyl paraben (MeP) and butyl paraben (BuP)) and their transformation products in indoor dust from different categories of settlement (urban, semi-urban, rural, and tribal homes). The results revealed a prevalent occurrence of parabens in all the settlement categories. A non-normal distribution pattern for MeP and BuP levels across the sampling sites was noted. While comparing the residence time of parabens in dust samples, it was found that the half-lives of the analytes were greater in the dust from urban (MeP t1/2: 47.510 h; BuP t1/2: 22.354 h) and rural (MeP t1/2: 27.725 h and BuP t1/2: 31.500 h) areas. The presence of paraben metabolites, such as hydroxy methylparaben (OH-MeP), para hydroxy benzoic acid (p-HBA), and benzoic acid (BA) in dust samples supports their transformation within indoor spaces. The average daily intake of parabens through dust ingestion and dermal absorption by children was higher than adults. BuP was the prime contributor (>85%) to the total estradiol equivalency quotient (tEEQ) in all the settlement categories.

Co-exposure to parabens, bisphenol A, and triclosan and the associations with dyslipidemia in Chinese older adults: the mediation effect of oxidative stress.

Dyslipidemia is a prevalent metabolic disorder in older adults and has negative effects on cardiovascular health. However, the combined effect of paraben, bisphenol A (BPA), and triclosan (TCS) exposure on dyslipidemia and the underlying mechanisms remain unclear. This cross-sectional study recruited 486 individuals ≥60 years in Shenzhen, China. Morning spot urine samples were collected and analyzed for four parabens, BPA, TCS, and 8-hydroxy-2'-deoxyguanosine (8-OHdG), a typical biomarker for oxidative stress, using mass spectrometry. Blood samples were tested for lipid levels using an automated biochemical analyzer. Quantile-based g-computation (QGC) was used to assess the combined effects of exposures on dyslipidemia. Mediation analysis was applied to investigate the mediating role of 8-OHdG between exposure and dyslipidemia. QGC showed that co-exposure to parabens, BPA, and TCS was positively linked with hypercholesterolemia (OR: 1.17, 95%CI: 1.10-1.24, P<0.001) and hyper-LDL-cholesterolemia (OR: 1.35, 95%CI: 1.05-1.75, P=0.019). Methylparaben (MeP), n-propyl paraben (PrP), and butylparaben (BtP) were the major contributors. 8-OHdG mediated 6.5% and 13.0% of the overall effect of the examined chemicals on hypercholesterolemia and hyper-LDL-cholesterolemia, respectively (all P<0.05). Our study indicated that co-exposure to parabens, BPA, and TCS is associated with dyslipidemia and oxidative stress partially mediate the association. Future research is needed to explore additional mechanisms underlying these relationships.

Efficient photocatalytic activity and selective adsorption of UiO-67 (Zr)/g-C3N4 composite toward a mixture of parabens.

In this study, UiO-67 (Zr)/g-C3N4 composites (U67N) were synthesized at wt.% ratios of 05:95, 15:85, and 30:70 using the solvothermal method at 80 °C for 24 h followed by calcination at 350 °C. The composites were characterized using UV-Vis diffuse reflectance spectroscopy, Fourier-transform infrared spectroscopy, photoluminescence spectroscopy, X-ray photoelectron spectroscopy, X-ray diffraction, scanning electron microscopy-energy-dispersive X-ray spectroscopy, transmission electron microscopy, and nitrogen physisorption analysis. In addition, thermal stability analysis of UiO-67 was conducted using thermogravimetric analysis. The photocatalytic performance of the composites was assessed during the degradation and mineralization of a mixture of methylparaben (MeP) and propylparaben (PrP) under simulated sunlight. The adsorption process of U67N 15:85 was characterized through kinetic studies and adsorption capacity experiments, which were modeled using pseudo-first-order and pseudo-second-order kinetics and Langmuir and Freundlich isotherms, respectively. The influence of pH levels 3, 5, and 7 on the photocatalytic degradation of the mixture was investigated, revealing enhanced degradation and mineralization at pH 3. The U67N composite exhibited dual capability in removing contaminants through adsorption and photocatalytic processes. Among the prepared composites, U67N 15:85 demonstrated the highest photocatalytic activity, achieving removal efficiencies of 96.8% for MeP, 92.5% for PrP, and 45.7% for total organic carbon in 300 kJ/m2 accumulated energy (3 h of reaction time). The detoxification of the effluent was confirmed through acute toxicity evaluation using the Vibrio fischeri method. The oxidation mechanism of the heterojunction formed between UiO-67 (Zr) and g-C3N4 was proposed based on PL analysis, photoelectrochemistry studies (including photocurrent response, Nyquist, and Mott-Schottky analyses), and scavenger assays.

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.

Urinary phenols and parabens exposure in relation to urinary incontinence in the US population.

BACKGROUND: Our study aimed to investigate the impact of urinary concentrations of personal care products (PCPs)-related phenols (PNs) and parabens (PBs), including Triclosan (TCS), Bisphenol A (BPA), Benzophenone-3 (BP-3), Butylparaben (BPB), Ethylparaben (EPB), Methylparaben (MPB), and Propylparaben (PPB), on urinary incontinence (UI) occurrence. METHOD: We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) spanning the years 2007 to 2016. Regression analysis was employed to investigate the relationship between exposure to PCPs-related substances, various levels of exposure, and UI within both the general population and the female demographic. Additionally, the Bayesian Kernel Machine Regression (BKMR) model was used to assess the effects of mixtures on UI. RESULTS: Our analysis comprised 7,690 participants who self-reported their diagnosis. Among them, 12.80% experienced stress urinary incontinence (SUI), 11.80% reported urge urinary incontinence (UUI), and 10.22% exhibited mixed urinary incontinence (MUI). In our fully adjusted multivariable models, BP-3 exposure exhibited a positive association with SUI (OR 1.07, 95% CI 1.02-1.14, p = 0.045). BPA exposure correlated with an increased risk of UUI (OR 1.21, 95% CI 1.01-1.44, p = 0.046) and MUI (OR 1.26, 95% CI 1.02-1.54, p = 0.029). TCS exposure displayed a negative correlation with the incidence of MUI (OR 0.87, 95% CI 0.79-0.97, p = 0.009). No significant links were observed between parabens and urinary incontinence. Notably, among the female population, our investigation revealed that BPA exposure heightened the risk of MUI (OR 1.28, 95% CI 1.01-1.63, p = 0.043). Participants in the highest tertile of BP-3 exposure demonstrated elevated likelihoods of SUI and MUI compared to those in the lowest tertile. In the BKMR analysis, negative trends were observed between the mixture and the risks of UUI and MUI when the mixture ranged from the 25th to the 40th and 35th to the 40th percentiles or above, respectively. Additionally, a positive trend was identified between the mixture and MUI when it was in the 40th to 55th percentile. CONCLUSION: In conclusion, our findings suggest that exposure to BPA, TCS, and BP-3 may contribute to the development of urinary incontinence.

Urinary paraben exposure increases the risk of a low estimated glomerular filtration rate in Taiwanese general population.

BACKGROUND: The inconsistent relationship between chemical exposure and estimated glomerular filtration rate (eGFR) has been examined in only a few studies. We investigated the association between paraben exposure and indicators of renal function in a total of 361 individuals recruiting from a representative study. METHOD: The levels of urinary parabens, including methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), and butylparaben (BuP), were measured using UPLC-MS/MS. The association between paraben exposure and indices of renal function was assessed using multiple logistic regression and Bayesian Kernel Machine Regression (BKMR). RESULTS: The median levels of urinary parabens in the adult group were significantly higher than those in the minor group, that is, 397 vs. 148 ng/mL for MeP, 38.8 vs. 13.6 ng/mL for EtP, 117 vs. 57.7 ng/mL for PrP, and 6.61 vs. 2.79 ng/mL for BuP (all P < 0.001). In the adult group, multivariate regression models confirmed a positive association between the albumin-to-creatinine ratio and urinary MeP (ß = 0.580) and a positive association of BUN (ß = 0.061) and a negative association of eGFR (ß = -0.051) with urinary EtP (all P < 0.001). In the adult group, compared with the lowest tertile group, the adjusted odds ratio in the third tertile (T3) of urinary EtP levels indicated a 3.08 times increased risk of eGFR abnormalities, followed by the second tertile (T2) with a 2.63 times increased risk. The generalized additive model (GAM) and BKMR models showed a non-linear correlation between urinary EtP levels and early CKD, as well as reduced eGFR. We observed a significant positive cumulative effect of urinary paraben on eGFR, and a significant positive single exposure effect of urinary EtP with eGFR abnormality. CONCLUSION: We found a significant association between exposure to EtP and an increased risk of high BUN levels and decreased eGFR.

Association of exposure to a mixture of phenols, parabens, and phthalates with altered serum thyroid hormone levels and the roles of iodine status and thyroid autoantibody status: A study among American adults.

BACKGROUND: Toxicological and epidemiological studies have shown that environmental endocrine disruptors interfere with hormonal homeostasis. However, there is limited research on the effects of mixed exposure to nonpersistent endocrine disruptors on thyroid hormones and the factors (e.g., presence status of thyroid autoantibodies or nutritional status of organismal iodine) that may influence this association. METHODS: Data were collected from the National Health and Nutrition Examination Survey (NHANES) 2007-2008 and 2011-2012. Relationships between single pollutants and thyroid hormone and thyroid autoantibody levels were assessed using generalized linear (GLM) and restricted cubic spline (RCS) regression models. Weighted quantile sum regression (WQS), group-weighted quantile sum regression (GWQS), quantile-based g-computation (qgcomp), and adaptive elasticity network (AENET) were applied to assess the mixed exposure effect. Next, subgroup analyses were performed on the basis of the urinary iodine concentration or thyroid autoantibody status to assess the modifying role of urinary iodine and thyroid autoantibodies. RESULTS: A total of 2385 study participants were included in this study. Both the single-pollutant model and the multipollutant mixed model revealed that parabens and bis(2-ethylhexyl) phthalate (DEHP) metabolites were significantly and negatively associated with serum thyroxine (T4) levels. However, no associations were found between the target pollutants and thyroid autoantibodies (thyroglobulin antibodies (TgAb) and thyroid peroxidase antibodies (TPOAb)). In addition, this study revealed that urinary iodine or thyroid autoantibody status altered the associations of some of the target pollutants with thyroid hormones. WQS and qgcomp analyses, revealed that the associations of mixed pollutants with hormones differed depending on the urinary iodine or antibody status, especially T4 and thyroid-stimulating hormone (TSH). CONCLUSION: Significant associations were found between phenols, parabens, and phthalates and serum thyroid hormone levels, with parabens and DEHP metabolites playing major roles. Urinary iodine and thyroid autoantibody status act as modifiers between environmental endocrine-disrupting pollutants and thyroid hormones.

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.

Co-Exposure to Bisphenols, Parabens, and Antimicrobials and Association with Coronary Heart Disease: Oxidative Stress as a Potential Mediating Factor?

Coronary heart disease (CHD) is the leading cause of global morbidity, but the effect of plasticizers and antimicrobial additives on CHD is unknown. Here, we conducted a case-control study to investigate the mediating role of oxidative stress in the association between co-exposure to seven bisphenols, four parabens, triclosan (TCS), triclocarban, and CHD risk in Guangzhou, China. Quantile-based g-computation and weighted quantile sum regression were used to analyze mixture-outcome associations. Quantile-based g-computation showed a positive joint effect of a decile increase in exposure to all examined pollutants on CHD risk (OR: 1.52, 95% CI: 1.25-1.84), with bisphenol A (BPA), bisphenol F (BPF), n-butyl paraben (BuP), and TCS representing major contributors. The results also showed a decile nonmonotonic increase in the exposure mixtures, positively correlated with a 2.22 ng/mL (95% CI: 1.21-3.23 ng/mL) elevation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), with BuP, TCS, bisphenol AP (BPAP), and BPF contributing dominantly. Mediation analysis showed that 8-OHdG mediated the relationship between BPA, BPF, BPAP, and TCS, and CHD risk. Moreover, the mediating role of high-density lipoprotein (HDL) between several bisphenols and CHD was also identified. It is yet to be verified, but bisphenols may elevate CHD risk by reducing HDL status and increasing oxidative stress.

Within-day variability, predictors, and risk assessments of exposure to parabens among Chinese adult men.

BACKGROUND: Parabens, as suspected endocrine disruptors, are widely used in personal care products and pharmaceuticals. However, variability, predictors, and risk assessments of human exposure to parabens are not well characterized. OBJECTIVE: To evaluate within-day variability, predictors, and risk assessments of exposure to parabens among Chinese adult men. METHODS: We measured four parabens including methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), and butylparaben (BuP) in repeated urine samples from 850 Chinese adult men. We examined the variability by intraclass correlation coefficients (ICCs) and identified the predictors by multivariable linear mixed models. We assessed risks of paraben exposures based on the estimated daily intake (EDI). RESULTS: The four parabens were detected in >76% of urinary samples. We observed fair to good to high reproducibility (ICCs: 0.71 to 0.86) for urinary paraben concentrations within one day. Use of facial cleanser was associated with higher four urinary paraben concentrations. Increasing age, taking medicine, intravenous injection, and interior decoration in the workplace were related to higher urinary concentrations of specific parabens. Smoking and drinking were associated with lower urinary concentrations of specific parabens. The maximum EDIs for the four parabens ranged from 13.76 to 848.68 µg/kg bw/day, and 0.9% of participants had the hazard quotient values > 1 driven by PrP exposure. CONCLUSIONS: Urinary paraben concentrations were less variable within one day. Several lifestyle characteristics including use of facial cleanser and pharmaceuticals may contribute to paraben exposures.

Association between chemical mixtures and female fertility in women undergoing assisted reproduction in Sweden and Estonia.

OBJECTIVE: Women of reproductive age are exposed to ubiquitous chemicals such as phthalates, parabens, and per- and polyfluoroalkyl substances (PFAS), which have potential endocrine disrupting properties and might affect fertility. Our objective was to investigate associations between potential endocrine-disrupting chemicals (EDCs) and female fertility in two cohorts of women attending fertility clinics. METHODS: In a total population of 333 women in Sweden and Estonia, we studied the associations between chemicals and female fertility, evaluating ovarian sensitivity index (OSI) as an indicator of ovarian response, as well as clinical pregnancy and live birth from fresh and frozen embryo transfers. We measured 59 chemicals in follicular fluid samples and detected 3 phthalate metabolites, di-2-ethylhexyl phthalate (DEHP) metabolites, 1 paraben, and 6 PFAS in >90% of the women. Associations were evaluated using multivariable-adjusted linear or logistic regression, categorizing EDCs into quartiles of their distributions, as well as with Bayesian Kernel Machine Regression. RESULTS: We observed statistically significant lower OSI at higher concentrations of the sum of DEHP metabolites in the Swedish cohort (Q4 vs Q1, ß = -0.21, 95% CI: -0.38, -0.05) and methylparaben in the Estonian cohort (Q3 vs Q1, ß = -0.22, 95% CI: -0.44, -0.01). Signals of potential associations were also observed at higher concentrations of PFUnDA in both the combined population (Q2 vs. Q1, ß = -0.16, 95% CI -0.31, -0.02) and the Estonian population (Q2 vs. Q1, ß = -0.27, 95% CI -0.45, -0.08), and for PFOA in the Estonian population (Q4 vs. Q1, ß = -0.31, 95% CI -0.61, -0.01). Associations of chemicals with clinical pregnancy and live birth presented wide confidence intervals. CONCLUSIONS: Within a large chemical mixture, we observed significant inverse associations levels of DEHP metabolites and methylparaben, and possibly PFUnDA and PFOA, with OSI, suggesting that these chemicals may contribute to altered ovarian function and infertility in women.

Binding of common organic UV-filters to the thyroid hormone transport protein transthyretin using in vitro and in silico studies: Potential implications in health.

Several anthropogenic contaminants have been identified as competing with the thyroid hormone thyroxine (T4) for binding to transport proteins as transthyretin (TTR). This binding can potentially create toxicity mechanisms posing a threat to human health. Many organic UV filters (UVFs) and paraben preservatives (PBs), widely used in personal care products, are chemicals of emerging concern due to their adverse effects as potential thyroid-disrupting compounds. Recently, organic UVFs have been found in paired maternal and fetal samples and PBs have been detected in placenta, which opens the possibility of the involvement of TTR in the transfer of these chemicals across physiological barriers. We aimed to investigate a discrete set of organic UVFs and PBs to identify novel TTR binders. The binding affinities of target UVFs towards TTR were evaluated using in vitro T4 competitive binding assays. The ligand-TTR affinities were determined by isothermal titration calorimetry (ITC) and compared with known TTR ligands. In parallel, computational studies were used to predict the 3-D structures of the binding modes of these chemicals to TTR. Some organic UVFs, compounds 2,2',4,4'-tetrahydroxybenzophenone (BP2, Kd = 0.43 µM); 2,4-dihydroxybenzophenone (BP1, Kd = 0.60 µM); 4,4'-dihydroxybenzophenone (4DHB, Kd = 0.83 µM), and 4-hydroxybenzophenone (4HB, Kd = 0.93 µM), were found to display a high affinity to TTR, being BP2 the strongest TTR binder (ΔH = -14.93 Kcal/mol). Finally, a correlation was found between the experimental ITC data and the TTR-ligand docking scores obtained by computational studies. The approach integrating in vitro assays and in silico methods constituted a useful tool to find TTR binders among common organic UVFs. Further studies on the involvement of the transporter protein TTR in assisting the transplacental transfer of these chemicals across physiological barriers and the long-term consequences of prenatal exposure to them should be pursued.

Development of a new strategy for the synthesis of graphene oxide-alumina nanocomposite as an efficient adsorbent for dispersive solid-phase extraction of parabens.

The present study investigates the synthesis and application of the graphene oxide-alumina nanocomposite as a new adsorbent for the dispersive solid-phase extraction of three parabens and their determination using high-performance liquid chromatography-ultraviolet detection. The characterization of the synthesized material was accomplished and its size, morphology, chemical composition, porosity, and thermal stability were studied. Application of the proposed strategy for the synthesis of the nanocomposite resulted in the incorporation of Al2 O3 nanoparticles into graphene oxide nanosheets, further resulting in the exfoliation of graphene oxide nanosheets increasing their surface area. An orthogonal rotatable central composite design was used to optimize the extraction. Under the optimum conditions, the analytical performance of the method showed a suitable linear dynamic range (0.2-100.0 µg/L), reasonable limits of detection (0.03-0.05 µg/L), and preconcentration factors ranging from 128 to 173. Finally, the new validated method was applied for the determination of parabens in some real samples including wastewater, cream, toothpaste, and juice samples with satisfactory recoveries (88%-109%), and relative standard deviations less than 8.7% (n = 3). Results demonstrated that inserting alumina nanoparticles into graphene oxide nanosheets improved the extraction efficiency of parabens, as polar acidic compounds, by providing additional efficient interactions including hydrogen bonding, dipole-dipole, and Brønsted and Lewis acid-base interactions.

Health safety of parabens evaluated by selected in vitro methods.

Seven selected parabens (4 allowed, 3 banned in cosmetics) were tested in order to confirm and expand historical data on their toxicological properties and safety. The aim was to apply novel in vitro methods, which have been sufficiently technically and scientifically validated for the purposes of toxicological testing of chemicals. The study included several toxicological endpoints such as skin/eye irritation, skin sensitization, endocrine disruption and genotoxicity. The battery of selected methods comprised regulatory accepted EpiDerm™ skin model (OECD TG 439); EpiOcular™ corneal model (OECD TG 492) and scientifically valid test method HET-CAM (DB-ALM Protocol No. 47); in chemico test DPRA (OECD TG 442C); in vitro test LuSens (OECD TG 442D) and in vitro test h-CLAT (OECD TG 442E); Ames MPF™ (Xenometrix) and XenoScreen YES/YAS (Xenometrix). Overall, none of the 4 allowed parabens exhibited skin/eye irritation or genotoxicity. However, all allowed parabens in cosmetics were predicted as samples with potentially sensitizing properties in the LuSens and h-CLAT test methods, but not confirmed by DPRA. Endocrine disruption was recorded only at high concentrations, whereas methyl paraben and ethyl paraben exhibited the lowest activity. This study confirmed the safety of use of the allowed parabens in the highest recommended concentrations in cosmetics or pharmaceuticals.

Reproductive toxicity of maternal exposure to di(2-ethylhexyl)phthalate and butyl paraben (alone or in association) on both male and female Wistar offspring.

Parabens and phthalates are commonly found as contaminants in human fluids and are able to provoke reproductive toxicity, being considered endocrine disruptors. To evaluate the effects of phthalate and paraben, alone or in combination, on reproductive development of the offspring, female pregnant Wistar rats were allocated in six experimental groups: Three control groups (gavage [CG], subcutaneous [CS], and gavage + subcutaneous) received corn oil as vehicle, and the remaining groups were exposed to di(2-ethylhexyl)phthalate (DEHP) (500 mg/kg, gavage), butyl paraben (BP) (100 mg/kg, subcutaneously), or MIX (DEHP + BP), from Gestational Day 12 until Postnatal Day (PND) 21. The following parameters were assessed on the offspring: anogenital distance and weight at PND 1, nipple counting at PND 13, puberty onset, estrous cycle, weights of reproductive and detoxifying organs, histological evaluation of reproductive organs, and sperm evaluations (counts, morphology, and motility). Female pups from MIX group presented reduced body weight at PND 1, lower AGD, and decreased endometrium thickness. Male animals showed decreased body weight at PND 1 and lower number of Sertoli cells on DEHP and MIX groups, MIX group revealed increase of abnormal seminiferous tubules, DEHP animals presented delayed preputial separation and higher percentage of immotile sperms, and BP males presented diminished number of Leydig cells. In conclusion, the male offspring was more susceptible to DEHP toxicity; even when mixed to paraben, the main negative effects observed seem to be due to antiandrogenic phthalate action. On the other hand, DEHP seems to be necessary to improve the effects of BP on reducing estrogen-dependent and increasing androgen-dependent events.

Evaluation of multigenerational effects of 2-ethylhexyl 4-hydroxybenzoate in Japanese medaka.

The Japanese medaka (Oryzias latipes) extended one-generation reproduction test (MEOGRT) (Test Guideline 890.2200) is a Tier 2 test within the Endocrine Disruptor Screening Program of the US Environmental Protection Agency (US EPA). A modified MEOGRT was used to evaluate multigenerational effects of 2-ethylhexyl 4-hydroxybenzoate (2-EHHB) under flow-through conditions starting with adults (parent generation, F0) through a 3-week reproductive phase of the second generation (F2). Fish were exposed to one of five 2-EHHB test concentrations or a dechlorinated tap water control. Fecundity was affected at the lowest exposure (5.32 µg/L) and greater sensitivity occurred in the F1 and F2 generations. Percent fertility was also diminished from no effect level observed in the F0 generation to 101 and 48.8 µg/L in the F1 and F2 generations, respectively. Growth indices were decreased for F0 adult females and F1 subadults and adults at 48.8 µg/L 2-EHHB. Histopathologic examination of gonads, liver, kidney, and thyroid yielded possible delayed reproductive tract development in F1 subadult males, masculinization of the renal phenotype in F1 adult females (renal tubular eosinophilia) and reduced hepatic energy storage (liver glycogen vacuoles) in F1 (11.3 and 48.8 µg/L) and F2 (48.8 and 101 µg/L) males and females, respectively. Endocrine-related findings included a decrease in anal fin papillae in F2 adult males at 101 µg/L. Results of this study demonstrate effects on growth, development, and reproduction that may be mediated by endocrine (weak estrogenic) and nonendocrine mechanisms. Duration of the MEOGRT should not be routinely extended beyond the OCSPP 890 guideline study design.