Environmental Chemical Exposures Research Articles

Reproductive and Metabolic Health Following Exposure to Environmental Chemicals: Mechanistic Insights from Mammalian Models.

The decline in human reproductive and metabolic health over the past 50years is associated with exposure to complex mixtures of anthropogenic environmental chemicals (ECs). Real-life EC exposure has varied over time and differs across geographical locations. Health-related issues include declining sperm quality, advanced puberty onset, premature ovarian insufficiency, cancer, obesity, and metabolic syndrome. Prospective animal studies with individual and limited EC mixtures support these observations and provide a means to investigate underlying physiological and molecular mechanisms. The greatest impacts of EC exposure are through programming of the developing embryo and/or fetus, with additional placental effects reported in eutherian mammals. Single-chemical effects and mechanistic studies, including transgenerational epigenetic inheritance, have been undertaken in rodents. Important translational models of human exposure are provided by companion animals, due to a shared environment, and sheep exposed to anthropogenic chemical mixtures present in pastures treated with sewage sludge (biosolids). Future animal research should prioritize EC mixtures that extend beyond a single developmental stage and/or generation. This would provide a more representative platform to investigate genetic and underlying mechanisms that explain sexually dimorphic and individual effects that could facilitate mitigation strategies.

Organophosphorus Flame Retardants and Metabolic Disruption: An in Silico, in Vitro, and in Vivo Study Focusing on Adiponectin Receptors.

Environmental chemical exposures have been associated with metabolic outcomes, and typically, their binding to nuclear hormone receptors is considered the molecular initiating event (MIE) for a number of outcomes. However, more studies are needed to understand the influence of such exposures on cell membrane-bound adiponectin receptors (AdipoRs), which are critical metabolic regulators. We aimed to clarify the potential interactions between AdipoRs and environmental chemicals, specifically organophosphorus flame retardants (OPFRs), and the resultant effects. Employing in silico simulation, cell thermal shift, and noncompetitive binding assays, we screened eight OPFRs for interactions with AdipoR1 and AdipoR2. We tested two key events underlying AdipoR modulation upon OPFR exposure in a liver cell model. The Toxicological Prioritization Index (ToxPi)scoring scheme was used to rank OPFRs according to their potential to disrupt AdipoR-associated metabolism. We further examined the inhibitory effect of OPFRs on AdipoR signaling activation in mouse models. Analyses identified pi-pi stacking and pi-sulfur interactions between the aryl-OPFRs 2-ethylhexyl diphenyl phosphate (EHDPP), triphenyl phosphate (TPhP), and tricresyl phosphate (TCP) and the transmembrane cavities of AdipoR1 and AdipoR2. Cell thermal shift assays showed a rightward shift in the AdipoR proteins' melting curves upon exposure to these three compounds. Although the binding sites differed from adiponectin, results suggest that aryl-OPFRs noncompetitively inhibited the binding of the endogenous peptide ligand ADP355 to the receptors. Analyses of key events underlying AdipoR modulation revealed that glucose uptake was notably lower, whereas lipid content was higher in cells exposed to aryl-OPFRs. EHDPP, TCP, and TPhP were ranked as the top three disruptors according to the ToxPi scores. A noncompetitive binding between these aryl-OPFRs and AdipoRs was also observed in wild-type (WT) mice. In db/db mice, the finding of lower blood glucose levels after ADP355 injection was diminished in the presence of a typical aryl-OPFR (TCP). WT mice exposed to TCP demonstrated lower AdipoR1 signaling, which was marked by lower phosphorylated AMP-activated protein kinase (pAMPK) and a higher expression of gluconeogenesis-related genes. Moreover, WT mice exposed to ADP355 demonstrated higher levels of pAMPK protein and peroxisome proliferator-activated receptor- messenger RNA. This was accompanied by higher glucose disposal and by lower levels of long-chain fatty acids and hepatic triglycerides; these metabolic improvements were negated upon TCP co-treatment. In silico, in vitro, and invivo assays suggest that aryl-OPFRs act as noncompetitive inhibitors of AdipoRs, preventing their activation by adiponectin, and thus function as antagonists to these receptors. Our study describes a novel MIE for chemical-induced metabolic disturbances and highlights a new pathway for environmental impact on metabolic health. https://doi.org/10.1289/EHP14634.

Impact of polyfluoroalkyl chemicals and volatile organic compounds exposure on lung function of American adults

BackgroundEnvironmental chemicals, such as Perfluoroalkyl and polyfluoroalkyl substances (PFAS) and volatile organic compounds (VOCs), and the association between the combined exposure of these chemicals and human lung function remains unclear. This study aimed to explore the effects of mixed exposure to PFAS and VOCs on lung function in the general population of the United States and investigate their potential mechanisms. MethodsData from 30442 respondents were selected for analysis during the US National Health and Nutrition Examination Survey (NHANES) database from 2007 to 2012. Linear models, weighted quantile (WQS) regression, quantile g calculation (QGC), and Bayesian kernel machine regression (BKMR) were used to evaluate the contribution of individual components. Moreover, the interactions between substances in the dose-response relationship mixture of multiple environmental chemical exposures and lung function were also evaluated. The Benjamini-Hochberg method was used to correct multiple tests. FindingsUnivariate analysis showed that nitromethane was negatively correlated with FEV1 (β =−0.052), FVC (β =−0.056), and PEF (β =−0.065), while perfluorohexanesulfonic acid was positively associated with FEV1 (β = 0.026), FVC (β = 0.024), FEF25-75% (β = 0.012), and PEF (β = 0.029). Multivariate analysis showed that chloroform and perfluorohexane sulfonic acid were positively associated with lung function (P <0.05), and perfluorohexane sulfonic acid contributed the most. Nitromethane and perfluorodecanoic acid were negatively associated with lung function (P < 0.05), and perfluorodecanoic acid contributed the highest weight in the negative direction. When all chemicals were in the 50th percentile, the environmental chemical mixture had no significant consistent effect or dose-response on lung function. There were interactions among various environmental chemicals within the mixture except for 2-N-methyl-PFOSA acetate and bromodichloromethane. InterpretationThese results suggest that environmental mixture exposure is associated with abnormal lung function in American adults, and the interaction of various substances in the mixture affects its physiological and chemical effects.

Environmental chemical exposures and a machine learning-based model for predicting hypertension in NHANES 2003–2016

BackgroundHypertension is a common disease, often overlooked in its early stages due to mild symptoms. And persistent elevated blood pressure can lead to adverse outcomes such as coronary heart disease, stroke, and kidney disease. There are many risk factors that lead to hypertension, including various environmental chemicals that humans are exposed to, which are believed to be modifiable risk factors for hypertension.ObjectiveTo investigate the role of environmental chemical exposures in predicting hypertension.MethodsA total of 11,039 eligible participants were obtained from NHANES 2003–2016, and multiple imputation was used to process the missing data, resulting in 5 imputed datasets. 8 Machine learning algorithms were applied to the 5 imputed datasets to establish hypertension prediction models, and the average accuracy score, precision score, recall score, and F1 score were calculated. A generalized linear model was also built to predict the systolic and diastolic blood pressure levels.ResultsAll 8 algorithms had good predictions for hypertension, with Support Vector Machine (SVM) being the best, with accuracy, precision, recall, F1 scores and area under the curve (AUC) of 0.751, 0.699, 0.717, 0.708 and 0.822, respectively. The R2 of the linear model on the training and test sets was 0.28, 0.25 for systolic and 0.06, 0.05 for diastolic blood pressure.ConclusionsIn this study, relatively accurate prediction of hypertension was achieved using environmental chemicals with machine learning algorithms, demonstrating the predictive value of environmental chemicals for hypertension.

7395 Developmental Programming: Adverse Effects Of Prenatal Exposure To A Real-Life Environmental Chemical Mixture Via Biosolids On Ovarian Folliculogenesis In Adult Sheep

Abstract Disclosure: Y. Zhou: None. K.M. Halloran: None. M. Bellingham: None. N.P. Evans: None. R.G. Lea: None. K.D. Sinclair: None. V. Padmanabhan: None. The ovarian capacity to provide fertilizable oocytes, regulate folliculogenesis as well as activate and progress primordial follicles into preovulatory follicles are key contributing factors to female fertility and reproductive aging. In sheep, as in humans, while genetics play a role in establishing the ovarian reserve during fetal development, developmental insults such as inappropriate exposure to native steroids or environmental chemicals (ECs) can adversely impact the establishment of the ovarian reserve and, additionally can affect folliculogenesis. Considering humans are exposed to multiple ECs simultaneously which could have additive, synergistic, or antagonistic effects, real-life EC exposure models are needed to assess risks posed by EC exposure. Offspring from sheep grazed on biosolids-treated pasture offers one such real-life exposure model. Studies with day 140 fetuses found maternal exposure to a real-life EC mixture via biosolids increased the proportion of unhealthy transitory follicles (Lea et al., Sci Rep. 2016;6:22279). The present study tested if biosolids exposure during fetal life would impact folliculogenesis, follicle activation and follicle atresia during their adult life. Ovaries were derived from adult EasyCare ewes (age 31.4 ± 0.5 months) whose mothers were grazed on biosolids-treated (BTP, n=10) or inorganic fertilizer-treated (Control, n=10) pastures from preconception through to birth. Ovarian morphometry was undertaken to assess the distribution and health status of follicles. Follicular atresia was evaluated via the expression of Caspase-3, an apoptosis marker. Data analysis utilized Student's t-test for normally distributed variables and Mann-Whitney U tests for non-parametric comparisons. There were no differences in the absolute counts or the percentages of follicle classes at all stages of folliculogenesis, the density of primordial follicles in cortical tissue, or the follicular activation rate. An increase in the percentage of unhealthy activated follicles (post-primordial) was noted in the BTP group (p = 0.014), predominantly in the transitory stage (p = 0.021). Consistent with this, a higher density of Caspase-3 positive primary follicles was observed in the BTP group (p = 0.033). These findings indicate the adverse impacts of fetal exposure to an EC mixture via maternal biosolid exposure on the survival of early-stage activated follicles in adult sheep. The lack of difference in ovarian reserve between the control and BTP groups suggests compensatory mechanisms may be in place to prevent premature depletion of the ovarian reserve. Whether EC mixture exposure via biosolids also has an adverse effect on the quality of the surviving activated follicles remains to be determined. Funding source: NIH R01 ES030374. Presentation: 6/3/2024

Urinary biomarkers of environmental exposures and asthma morbidity in a school inner city asthma study

BackgroundThe burden of pediatric asthma and other allergic diseases is not evenly distributed among United States populations. ObjectiveTo determine whether urinary biomarkers are associated with asthma morbidity, and if associations vary by child race, ethnicity and sex. MethodsThis study includes n = 152 children with physician-diagnosed asthma who participated in the School Inner-City Asthma Intervention Study (SICAS-2). Metabolites of phenol, paraben, polycyclic aromatic hydrocarbons, and phthalate analytes were analyzed from urine samples collected at baseline. Asthma symptom days over the past 2 weeks were dichotomized to no asthma symptom days or any asthma symptom days. Cross-sectional regression models were adjusted for age, sex, number of colds, household income, prescription control, race and ethnicity, body mass index (BMI) percentile, and smoke exposure. Weighted quantile sum regression was used to analyze each chemical class and a total mixture effect, controlling for the same covariates. Analyses were conducted with the assistance of the National Institute of Environmental Health Sciences Children's Health Exposure Analysis Resource (CHEAR). ResultsParticipants were mostly Hispanic/Latino and low income with an average age of 7.83 years and the average maximum asthma symptom days over the past two weeks of 2.13 (standard deviation: 3.56). The maximum concentrations indicate extreme values for several chemicals, including bisphenol-3, 2,5-dichlorophenol, propyl and methyl parabens, triclosan, methyl paraben and cotinine. We found a significant interaction effect and differing contributions of analytes for children with allergen sensitivity versus those that did not. For stratified analyses assessing effect modification by child race and ethnicity, weighted quantile sum interaction models showed reduced odds of asthma symptoms to a greater magnitude in children of other races and ethnicities compared to Black, Non-Hispanic children. ConclusionsPreliminary analyses of the association between environmental chemical exposure and asthma symptoms among inner-city children revealed an inverse association, which may be due to personal care and medication use and can be understood further in future analyses. Beneficial effects were detected for most of the chemicals.

Chemical and non-chemical stressors in a postpartum cohort through wristband and self report data: Links between increased chemical burden, economic, and racial stress

Multiple external stressors are known to have adverse impacts on health and development. Certain groups are more vulnerable and/or more likely to be exposed toenvironmental, psychological, and social stressors simultaneously. Yet, few studies have examined combined exposure to environmental toxicants and psychosocial stress. Here, we integrated environmental chemical exposure data collected using silicone wristbands and self-report social stressor data within the Brain and Early Experience (BEE) perinatal cohort to understand co-exposure to environmental chemicals and social stress. Silicone wristbands were worn for one week by mothers throughout central North Carolina who were 6 months postpartum (n = 97). Exposure to 110 environmental chemicals across eight chemical classes was quantified on silicone wristbands using gas chromatography mass spectrometry. Social stress was evaluated using eight established self-report questionnaires (e.g., Brief Symptom Inventory, Perceived Stress Scale), quantifying experiences such as race-related stress, economic strain, and relationship conflict. Hair cortisol levels were measured as an additional metric of stress. The chemical exposure landscape and associations among chemical exposure, demographic characteristics, and social stress were characterized through individual variable analyses, cluster and data reduction, and compiled scoring approaches to comprehensively evaluate chemical and social stress burdens. We found that chemicals contain co-occurring patterns largely based on chemical class, with phthalates representing the chemical class with highest exposure and polychlorinated biphenyls the lowest. Chemicals showed differential exposure across racial groups, with diethyl phthalate, triphenyl phosphate, and tris(3,5-dimethyl phenyl) phosphate at higher levels in Black participants compared with White participants. Integrating social stressor profiling with chemical exposure data identified one particularly vulnerable subset of participants in which high chemical exposure burden coincided with high experiences of racism and economic stress. These findings demonstrate co-occurring chemical and social stress, warranting further investigation to better understand how these combined stressors may contribute to disparities in maternal and child health.

Recruitment strategies for studying occupational and environmental chemical exposures in a community-based birth cohort study in Ecuador

Recruitment strategies for studying occupational and environmental chemical exposures in a community-based birth cohort study in Ecuador

Searching the exposome to identify environmental chemical exposures for cancer risk in humans: the Southern Environmental Health Study

Searching the exposome to identify environmental chemical exposures for cancer risk in humans: the Southern Environmental Health Study

Associations of environmental chemical exposures measured in personal silicone wristbands with sociodemographic factors, COVID-19 restrictions, and child respiratory health

BackgroundAlthough human biomonitoring of environmental chemicals has been considered a gold standard, these methods can be costly, burdensome, and prone to unwanted sources of variability that may cause confounding. Silicone wristbands have recently emerged as innovative passive samplers for measuring personal exposures. MethodsIn a pilot study from 2019 to 2021 involving 55 children aged 5–9 years in Seattle and Yakima, Washington, we utilized silicone wristbands to explore associations of sociodemographic variables and COVID-19-related restrictions, including school closures, with exposures to numerous chemicals including brominated and organophosphate ester (OPE) flame retardants, polychlorinated biphenyls, polycyclic aromatic hydrocarbons (PAHs), phthalates, and pesticides. We additionally conducted the first analysis testing silicone wristband chemicals as predictors of child wheeze, individually and in mixtures via logistic weighted quantile sum regression (WQS). ResultsAmong 109 semi-volatile organic compounds measured, we detected 40 in >60% of wristbands worn by children continuously for an average of 5 days. Chemicals were generally positively correlated, especially within the same class. Male sex and increasing age were linked with higher exposures across several chemical classes; Hispanic/Latino ethnicity was linked with higher exposures to some phthalates and OPEs. COVID-19 restrictions were associated with lower wristband concentrations of brominated and triaryl OPE flame retardants. Each one-decile higher WQS exposure index was suggestively associated with 2.11-fold [95% CI: 0.93–4.80] higher odds of child wheeze. Risk of child wheeze was higher per 10-fold increase in the PAH chrysene (RR = 1.93[1.07–3.49]), the pesticide cis-permethrin (3.31[1.23–8.91]), and di-isononyl phthalate (DINP) (5.40[1.22–24.0]) ConclusionsOur identification of demographic factors including sex, age, and ethnicity associated with chemical exposures may aid efforts to mitigate exposure disparities. Lower exposures to flame retardants during pandemic restrictions corroborates prior evidence of higher levels of these chemicals in school versus home environments. Future research in larger cohorts is needed to validate these findings.

Erratum: Novel, Plastic-Free Vaginal Applicator for Reduction of Environmental and Systemic Plastic Chemical Exposures That Associate With Cancers.

Erratum: Novel, Plastic-Free Vaginal Applicator for Reduction of Environmental and Systemic Plastic Chemical Exposures That Associate With Cancers.

Integrated Transfer Learning and Multitask Learning Strategies to Construct Graph Neural Network Models for Predicting Bioaccumulation Parameters of Chemicals.

Accurate prediction of parameters related to the environmental exposure of chemicals is crucial for the sound management of chemicals. However, the lack of large data sets for training models may result in poor prediction accuracy and robustness. Herein, integrated transfer learning (TL) and multitask learning (MTL) was proposed for constructing a graph neural network (GNN) model (abbreviated as TL-MTL-GNN model) using n-octanol/water partition coefficients as a source domain. The TL-MTL-GNN model was trained to predict three bioaccumulation parameters based on enlarged data sets that cover 2496 compounds with at least one bioaccumulation parameter. Results show that the TL-MTL-GNN model outperformed single-task GNN models with and without the TL, as well as conventional machine learning models trained with molecular descriptors or fingerprints. Applicability domains were characterized by a state-of-the-art structure-activity landscape-based (abbreviated as ADSAL) methodology. The TL-MTL-GNN model coupled with the optimal ADSAL was employed to predict bioaccumulation parameters for around 60,000 chemicals, with more than 13,000 compounds identified as bioaccumulative chemicals. The high predictive accuracy and robustness of the TL-MTL-GNN model demonstrate the feasibility of integrating the TL and MTL strategy in modeling small-sized data sets. The strategy holds significant potential for addressing small data challenges in modeling environmental chemicals.

Medaka liver developed Human NAFLD-NASH transcriptional signatures in response to ancestral bisphenol A exposure.

The progression of fatty liver disease to non-alcoholic steatohepatitis (NASH) is a leading cause of death in humans. Lifestyles and environmental chemical exposures can increase the susceptibility of humans to NASH. In humans, the presence of bisphenol A (BPA) in urine is associated with fatty liver disease, but whether ancestral BPA exposure leads to the activation of human NAFLD-NASH-associated genes in the unexposed descendants is unclear. In this study, using medaka fish as an animal model for human NAFLD, we investigated the transcriptional signatures of human NAFLD-NASH and their associated roles in the pathogenesis of the liver of fish that were not directly exposed, but their ancestors were exposed to BPA during embryonic and perinatal development three generations prior. Comparison of bulk RNA-Seq data of the liver in BPA lineage male and female medaka with publicly available human NAFLD-NASH patient data revealed transgenerational alterations in the transcriptional signature of human NAFLD-NASH in medaka liver. Twenty percent of differentially expressed genes (DEGs) were upregulated in both human NAFLD patients and medaka. Specifically in females, among the total shared DEGs in the liver of BPA lineage fish and NAFLD patient groups, 27.69% were downregulated, and 20% were upregulated. Of all DEGs, 52.31% of DEGs were found in ancestral BPA-lineage females, suggesting that NAFLD in females shared the majority of human NAFLD gene networks. Pathway analysis revealed beta-oxidation, lipoprotein metabolism, and HDL/LDL-mediated transport processes linked to downregulated DEGs in BPA lineage males and females. In contrast, the expression of genes encoding lipogenesis-related proteins was significantly elevated in the liver of BPA lineage females only. BPA lineage females exhibiting activation of myc, atf4, xbp1, stat4, and cancerous pathways, as well as inactivation of igf1, suggest their possible association with an advanced NAFLD phenotype. The present results suggest that gene networks involved in the progression of human NAFLD and the transgenerational NAFLD in medaka are conserved and that medaka can be an excellent animal model to understand the development and progression of liver disease and environmental influences in the liver.

A Personalized Intervention to Increase Environmental Health Literacy and Readiness to Change in a Northern Nevada Population: Effects of Environmental Chemical Exposure Report-Back.

Interventions are needed to help people reduce exposure to harmful chemicals from everyday products and lifestyle habits. Report-back of individual exposures is a potential pathway to increasing environmental health literacy (EHL) and readiness to reduce exposures. Our objective was to determine if report-back of endocrine-disrupting chemicals (EDCs) can reduce EDC exposure, increase EHL, and increase readiness to change (i.e., to implement EDC exposure-reduction behaviors). Participants in the Healthy Nevada Project completed EHL and readiness-to-change surveys before (n = 424) and after (n = 174) a report-back intervention. Participants used mail-in kits to measure urinary biomarkers of EDCs. The report-back of results included urinary levels, information about health effects, sources of exposure, and personalized recommendations to reduce exposure. EHL was generally very high at baseline, especially for questions related to the general pollution. For questions related to chemical exposures, responses varied across several demographics. Statistically reliable improvements in EHL responses were seen after report-back. For readiness to change, 72% were already or planning to change their behaviors. Post-intervention, women increased their readiness (p = 0.053), while men decreased (p = 0.007). When asked what challenges they faced in reducing exposure, 79% cited not knowing what to do. This dropped to 35% after report-back. Participants with higher propylparaben were younger (p = 0.03) and women and participants who rated themselves in better health had higher levels of some phthalates (p = 0.02-0.003 and p = 0.001-0.003, respectively). After report-back, monobutyl phthalate decreased among the 48 participants who had valid urine tests before and after the intervention (p < 0.001). The report-back intervention was successful as evidenced by increased EHL behaviors, increased readiness to change among women, and a decrease in monobutyl phthalate. An EHL questionnaire more sensitive to chemical exposures would help differentiate high and low literacy. Future research will focus on understanding why men decreased their readiness to change and how the intervention can be improved for all participants.

Gestational exposure to organochlorine compounds and metals and infant birth weight: effect modification by maternal hardships

BackgroundGestational exposure to toxic environmental chemicals and maternal social hardships are individually associated with impaired fetal growth, but it is unclear whether the effects of environmental chemical exposure on infant birth weight are modified by maternal hardships.MethodsWe used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort of 1982 pregnant females enrolled between 2008 and 2011. We quantified eleven environmental chemical concentrations from two chemical classes – six organochlorine compounds (OCs) and five metals – that were detected in ≥ 70% of blood samples collected during the first trimester. We examined fetal growth using birth weight adjusted for gestational age and assessed nine maternal hardships by questionnaire. Each maternal hardship variable was dichotomized to indicate whether the females experienced the hardship. In our analysis, we used elastic net to select the environmental chemicals, maternal hardships, and 2-way interactions between maternal hardships and environmental chemicals that were most predictive of birth weight. Next, we obtained effect estimates using multiple linear regression, and plotted the relationships by hardship status for visual interpretation.ResultsElastic net selected trans-nonachlor, lead, low educational status, racially minoritized background, and low supplemental folic acid intake. All were inversely associated with birth weight. Elastic net also selected interaction terms. Among those with increasing environmental chemical exposures and reported hardships, we observed stronger negative associations and a few positive associations. For example, every two-fold increase in lead concentrations was more strongly associated with reduced infant birth weight among participants with low educational status (β = -100 g (g); 95% confidence interval (CI): -215, 16), than those with higher educational status (β = -34 g; 95% CI: -63, -3). In contrast, every two-fold increase in mercury concentrations was associated with slightly higher birth weight among participants with low educational status (β = 23 g; 95% CI: -25, 71) compared to those with higher educational status (β = -9 g; 95% CI: -24, 6).ConclusionsOur findings suggest that maternal hardships can modify the associations of gestational exposure to some OCs and metals with infant birth weight.

Novel, Plastic-Free Vaginal Applicator for Reduction of Environmental and Systemic Plastic Chemical Exposures That Associate With Cancers

PURPOSE A cost-effective, prebiotic gel (PreBioGyn) is being developed to prevent genital cancers by reducing biological risk factors for women including vaginal infections, mucosal inflammation, and plastic contaminant exposure. PreBioGyn is packaged in a reduced-plastic system, using a Kraft-paper vaginal applicator. Vaginal mucosa has high absorption and permeability putting women at risk to contaminants in feminine-care products. Specifically, cell toxic levels of phthalates and bisphenols are found in 90% of these products with increased serum levels (e.g. 5X) occurring in some users. Short-term exposure to plastics used in these products results in over 5,000 leachable chemicals migrating into water samples. Plastic chemical burdens are amplified for women in low-resource settings, women who also have increased genital cancer risks. These studies evaluated the dosing accuracy, user acceptance, and cytotoxicity of the paper PreBioGyn applicator. METHODS (1) Dosing accuracy of the paper applicator was compared to that of plastic applicators used with existing vaginal gels (Trimosan and RepHresh; modified ISO11608-1:2014). (2) Table-top acceptability of the paper applicator was scored by 42 HPV-positive women in two locations (BWH and UPRMSC). Women were not educated about any benefits of plastic-free vaginal applicators. (3) Cytotoxicity of the paper applicator was tested (ISO 10993-1:2018, 10993-5:2009, 10993-12:2012) with 48 hr extract exposure to L929 cells. Latex glove extracts served as positive controls. RESULTS For the PreBioGyn paper applicator: (1) 90% of gel doses fell within target levels (+10%) which was significantly more accurate as compared to the two plastic applicators. (2) The proportion of women who scored the applicator in Likert responses as neutral or better (vs a negative acceptance score) was &gt;50% for appearance, feel, and dose-preparation; and &gt;64% for use with vaginal medications as part of a cancer prevention program. (3) No cytotoxicity or biological reactivity was seen in applicator extracts. Latex extracts resulted in severe destruction of cells. CONCLUSION The novel paper applicator was safe, effective and acceptable in these studies. Acceptability was equal to published ratings for many plastic applicators used in existing vaginal products. The reduced-plastic PreBioGyn delivery system is designed to minimize plastic contaminant exposure in the vagina and the environment, further supporting its adoption as a cancer prevention gel.

Healthy dietary patterns are associated with exposure to environmental chemicals in a pregnancy cohort

Healthy dietary patterns, such as the alternate Mediterranean diet and alternate Healthy Eating Index, benefit cardiometabolic health. However, several food components of these dietary patterns are primary sources of environmental chemicals. Here, using data from a racially and ethnically diverse US cohort, we show that healthy dietary pattern scores were positively associated with plasma chemical exposure in pregnancy, particularly for the alternate Mediterranean diet and alternate Healthy Eating Index with polychlorinated biphenyls and per- and poly-fluoroalkyl substances. The associations appeared stronger among Asian and Pacific Islanders. These findings suggest that optimizing the benefits of a healthy diet requires concerted regulatory efforts aimed at lowering environmental chemical exposure.

Associations between urinary hydroxylated polycyclic aromatic hydrocarbon biomarker concentrations and measures of timing of delivery and infant size at birth

Preterm birth is a leading cause of neonatal mortality and presents significant public health concerns. Environmental chemical exposures during pregnancy may be partially to blame for disrupted delivery timing. Polycyclic aromatic hydrocarbons (PAHs) are products of incomplete combustion, exposure to which occurs via inhalation of cigarette smoke and automobile exhaust, and ingestion of charred meats. Exposure to PAHs in the US population is widespread, and pregnant women represent a susceptible population to adverse effects of PAHs. We aimed to investigate associations between gestational exposure to PAHs and birth outcomes, including timing of delivery and infant birth size. We utilized data from the PROTECT birth cohort where pregnant women provided spot urine samples at up to three study visits (median 16, 20, and 24 weeks gestation). Urine samples were assayed for eight hydroxylated PAH concentrations. Associations between PAHs and birth outcomes were calculated using linear/logistic regression models, with adjustment for maternal age, education, pre-pregnancy BMI, and daily exposure to environmental tobacco smoke. Models accounted for urine dilution using specific gravity. We also explored effect modification by infant sex. Interquartile range (IQR) increases in all averaged PAH exposures during the second trimester were associated with reduced gestational age at delivery and increased odds of overall PTB, although these associations were not statistically significant (p > 0.05). Most PAHs at the second study visit were most strongly associated with earlier delivery and increased odds of overall and spontaneous PTB, with visit 2 2-hydroxynapthalene (2-NAP) being significantly associated with increased odds of overall PTB (OR:1.55; 95 %CI: 1.05,2.29). Some PAHs resulted in earlier timing of delivery among only female fetuses, specifically 2-NAP on overall PTB (female OR:1.52 95 %CI: 1.02,2.27; male OR:0.78, 95 %CI: 0.53,1.15). Future work should more deeply investigate differential physiological impacts of PAH exposure between pregnancies with male and female fetuses, and on varying developmental processes occurring at different points through pregnancy.

Rapid identification of reproductive toxicants among environmental chemicals using an in vivo evaluation of gametogenesis in budding yeast Saccharomyces cerevisiae

Infertility affects ∼12 % of couples, with environmental chemical exposure as a potential contributor. Of the chemicals that are actively manufactured, very few are assessed for reproductive health effects. Rodents are commonly used to evaluate reproductive effects, which is both costly and time consuming. Thus, there is a pressing need for rapid methods to test a broader range of chemicals. Here, we developed a strategy to evaluate large numbers of chemicals for reproductive toxicity via a yeast, S. cerevisiae high-throughput assay to assess gametogenesis as a potential new approach method (NAM). By simultaneously assessing chemicals for growth effects, we can distinguish if a chemical affects gametogenesis only, proliferative growth only or both. We identified a well-known mammalian reproductive toxicant, bisphenol A (BPA) and ranked 19 BPA analogs for reproductive harm. By testing mixtures of BPA and its analogs, we found that BPE and 17 β-estradiol each together with BPA showed synergistic effects that worsened reproductive outcome. We examined an additional 179 environmental chemicals including phthalates, pesticides, quaternary ammonium compounds and per- and polyfluoroalkyl substances and found 57 with reproductive effects. Many of the chemicals were found to be strong reproductive toxicants that have yet to be tested in mammals. Chemicals having affect before meiosis I division vs. meiosis II division were identified for 16 gametogenesis-specific chemicals. Finally, we demonstrate that in general yeast reproductive toxicity correlates well with published reproductive toxicity in mammals illustrating the promise of this NAM to quickly assess chemicals to prioritize the evaluation for human reproductive harm.

(002) PER- AND POLYFLUOROALKYL SUBSTANCES (PFAS) AND FEMALE SEXUAL FUNCTION IN A PRECONCEPTION COHORT

Abstract Introduction Per- and polyfluoroalkyl substances (PFAS) are prevalent environmental chemicals used extensively in consumer and industrial products. Distressing disruptions to sexual function are prevalent in reproductive-aged women, yet its etiology is incompletely characterized. PFAS could plausibly affect sexual function because they interfere with the production, metabolism, and secretion of reproductive hormones and have known neurotoxic properties. To our knowledge, however, no research to date has evaluated associations between PFAS exposure and female sexual function. Objective To evaluate associations between PFAS biomarker concentrations and female sexual function. Methods We used cross-sectional data from the Pregnancy Study Online (PRESTO; n=82), a preconception cohort study of female-identified pregnancy planners living in the United States or Canada, to estimate associations between PFAS biomarker concentrations and female sexual function, measured using 6 select items from the Female Sexual Function Index (FSFI). We summed scores from the FSFI items to create a sexual function score (range=0-30; median in PRESTO=22). Lower scores were indicative of worse sexual function. We measured concentrations of four PFAS (specifically PFOS, PFOA, PFNA, and PFHxS) in serum using isotope-dilution tandem mass spectrometry. We used multivariable linear regression to estimate mean differences in sexual function scores per interquartile range (IQR) increase in PFAS concentrations with 95% confidence intervals (CIs), adjusting for potential confounders. We stratified results by parity (parous vs. nulliparous) to evaluate the potential for effect modification by prior pregnancy, as placental transfer, menstruation, and lactation are known routes of PFAS elimination. Results Median serum PFAS concentrations (ng/mL) were 1.3, 1.1, 0.3, and 0.7 for PFOS, PFOA, PFNA, and PFHxS, respectively. An IQR increase in PFHxS was associated with a 1.4-point decrease (95% CI -2.1, -0.6) in sexual function scores, reflecting a ~5% change. Among parous participants, there was a consistent trend of decreased sexual function scores per IQR increase in PFAS concentrations. The strongest association was observed for PFOS, where an IQR increase in serum concentration was associated with a 4.9-point decrease in sexual function scores (95% CI -9.1, -0.6). Conclusions These preliminary findings indicate that higher serum PFAS concentrations are associated with decreased self-reported female sexual function. Prior research evaluating the relationship between environmental chemical exposures and sexual function have historically focused on male outcomes (e.g., semen quality). These fundings suggest value in expanding research focused on the sexual health consequences of endocrine disrupting chemicals to include female sexual function. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: LAW serves as a consultant to AbbVie, Inc.