Considerations and challenges in support of science and communication of fish consumption advisories for per- and polyfluoroalkyl substances.

Federal, state, tribal, or local entities in the United States issue fish consumption advisories (FCAs) as guidance for safer consumption of locally caught fish containing contaminants. Fish consumption advisories have been developed for commonly detected compounds such as mercury and polychlorinated biphenyls. The existing national guidance does not specifically address the unique challenges associated with bioaccumulation and consumption risk related to per- and polyfluoroalkyl substances (PFAS). As a result, several states have derived their own PFAS-related consumption guidelines, many of which focus on one frequently detected PFAS, known as perfluorooctane sulfonic acid (PFOS). However, there can be significant variation between tissue concentrations or trigger concentrations (TCs) of PFOS that support the individual state-issued FCAs. This variation in TCs can create challenges for risk assessors and risk communicators in their efforts to protect public health. The objective of this article is to review existing challenges, knowledge gaps, and needs related to issuing PFAS-related FCAs and to provide key considerations for the development of protective fish consumption guidance. The current state of the science and variability in FCA derivation, considerations for sampling and analytical methodologies, risk management, risk communication, and policy challenges are discussed. How to best address PFAS mixtures in the development of FCAs, in risk assessment, and establishment of effect thresholds remains a major challenge, as well as a source of uncertainty and scrutiny. This includes developments better elucidating toxicity factors, exposures to PFAS mixtures, community fish consumption behaviors, and evolving technology and analytical instrumentation, methods, and the associated detection limits. Given the evolving science and public interests informing PFAS-related FCAs, continued review and revision of FCA approaches and best practices are vital. Nonetheless, consistent, widely applicable, PFAS-specific approaches informing methods, critical concentration thresholds, and priority compounds may assist practitioners in PFAS-related FCA development and possibly reduce variability between states and jurisdictions. Integr Environ Assess Manag 2024;00:1-20. © 2024 SETAC.

PFAS ghosts: how to identify, evaluate, and exorcise new and existing analytical interference.

With increasing public awareness of PFAS, and their presence in biological and environmental media across the globe, comes a matching increase in the number of PFAS monitoring studies. As more matrices and sample cohorts are examined, there are more opportunities for matrix interferents to appear as PFAS where there are none (i.e., "seeing ghosts"), impacting subsequent reports. Addressing these ghosts is vital for the research community, as proper analytical measurements are necessary for decision-makers to understand the presence, levels, and potential risks associated with PFAS and protect human and environmental health. To date, PFAS interference has been identified in several matrices (e.g., food, shellfish, blood, tissue); however, additional unidentified interferents are likely to be observed as PFAS research continues to expand. Therefore, the aim of this commentary is several fold: (1) to create and support a publicly available dataset of all currently known PFAS analytical interferents, (2) to allow for the expansion of that dataset as more sources of interference are identified, and (3) to advise the wider scientific community on how to both identify and eliminate current or new analytical interference in PFAS analyses.

Establishing performance metrics for quantitative non-targeted analysis: a demonstration using per- and polyfluoroalkyl substances.

Non-targeted analysis (NTA) is an increasingly popular technique for characterizing undefined chemical analytes. Generating quantitative NTA (qNTA) concentration estimates requires the use of training data from calibration "surrogates," which can yield diminished predictive performance relative to targeted analysis. To evaluate performance differences between targeted and qNTA approaches, we defined new metrics that convey predictive accuracy, uncertainty (using 95% inverse confidence intervals), and reliability (the extent to which confidence intervals contain true values). We calculated and examined these newly defined metrics across five quantitative approaches applied to a mixture of 29 per- and polyfluoroalkyl substances (PFAS). The quantitative approaches spanned a traditional targeted design using chemical-specific calibration curves to a generalizable qNTA design using bootstrap-sampled calibration values from "global" chemical surrogates. As expected, the targeted approaches performed best, with major benefits realized from matched calibration curves and internal standard correction. In comparison to the benchmark targeted approach, the most generalizable qNTA approach (using "global" surrogates) showed a decrease in accuracy by a factor of ~4, an increase in uncertainty by a factor of ~1000, and a decrease in reliability by ~5%, on average. Using "expert-selected" surrogates (n = 3) instead of "global" surrogates (n = 25) for qNTA yielded improvements in predictive accuracy (by ~1.5×) and uncertainty (by ~70×) but at the cost of further-reduced reliability (by ~5%). Overall, our results illustrate the utility of qNTA approaches for a subclass of emerging contaminants and present a framework on which to develop new approaches for more complex use cases.

Maternal and Neonatal Effects of Maternal Oral Exposure to Perfluoro-2-methoxyacetic Acid (PFMOAA) during Pregnancy and Early Lactation in the Sprague-Dawley Rat.

Perfluoro-2-methoxyacetic acid (PFMOAA) is a short-chain perfluoroalkyl ether carboxylic acid that has been detected at high concentrations (∼10 µg/L) in drinking water in eastern North Carolina, USA, and in human serum and breastmilk in China. Despite documented human exposure there are almost no toxicity data available to inform risk assessment of PFMOAA. Here we exposed pregnant Sprague-Dawley rats to a range of PFMOAA doses (10-450 mg/kg/d) via oral gavage from gestation day (GD) 8 to postnatal day (PND) 2 and compared results to those we previously reported for perfluorooctanoic acid (PFOA) and hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX). Newborn pups displayed reduced birthweight (≥30 mg/kg), depleted liver glycogen concentrations (all doses), hypoglycemia (≥125 mg/kg), and numerous significantly altered genes in the liver associated with fatty acid and glucose metabolism similar to gene changes produced by HFPO-DA. Pup survival was significantly reduced at ≥125 mg/kg, and at necropsy on PND2 both maternal and neonatal animals displayed increased liver weights, increased serum aspartate aminotransferase (AST), and reduced serum thyroid hormones at all doses (≥10 mg/kg). Pups also displayed highly elevated serum cholesterol at all doses. PFMOAA concentrations in serum and liver increased with maternal oral dose in both maternal and F1 animals and were similar to those we reported for PFOA but considerably higher than HFPO-DA. We calculated 10% effect levels (ED10 or EC10) and relative potency factors (RPF; PFOA = index chemical) among the three compounds based on maternal oral dose and maternal serum concentration (µM). Reduced pup liver glycogen, increased liver weights and reduced thyroid hormone levels (maternal and pup) were the most sensitive end points modeled. PFMOAA was ∼3-7-fold less potent than PFOA for most end points based on maternal serum RPFs, but slightly more potent for increased maternal and pup liver weights. PFMOAA is a maternal and developmental toxicant in the rat producing a constellation of adverse effects similar to PFOA and HFPO-DA.

Extracellular Vesicles altered by a Per- and Polyfluoroalkyl Substance Mixture: In Vitro Dose-Dependent Release, Chemical Content, and MicroRNA Signatures involved in Liver Health.

Per- and polyfluoroalkyl substances (PFAS) have emerged as high priority contaminants due to their ubiquity and pervasiveness in the environment. Numerous PFAS co-occur across sources of drinking water, including areas of North Carolina (NC) with some detected concentrations above the Environmental Protection Agency's health advisory levels. While evidence demonstrates PFAS exposure induces harmful effects in the liver, the involvement of extracellular vesicles (EVs) as potential mediators of these effects has yet to be evaluated. This study set out to evaluate the hypothesis that PFAS mixtures induce dose-dependent release of EVs from liver cells, with exposures causing differential loading of microRNAs (miRNAs) and PFAS chemical signatures. To test this hypothesis, a defined PFAS mixture was prioritized utilizing data collected by the NC PFAS Testing Network. This mixture contained three substances, PFOS, PFOA, and PFHxA, selected based upon co-occurrence patterns and the inclusion of both short-chain (PFHxA) and long-chain (PFOA and PFOS) substances. HepG2 liver cells were exposed to equimolar PFAS, and secreted EVs were isolated from conditioned media and characterized for count and molecular content. Exposures induced a dose-dependent release of EVs carrying miRNAs that were differentially loaded upon exposure. These altered miRNA signatures were predicted to target mRNA pathways involved in hepatic fibrosis and cancer. Chemical concentrations of PFOS, PFOA, and PFHxA were also detected in both parent HepG2 cells and their released EVs, specifically within a 15-fold range after normalizing for protein content. This study therefore established EVs as novel biological responders and measurable endpoints for evaluating PFAS-induced toxicity.

Analytical method interferences for perfluoropentanoic acid (PFPeA) and perfluorobutanoic acid (PFBA) in biological and environmental samples.

While high-resolution MS (HRMS) can be used for identification and quantification of novel per- and polyfluorinated alkyl substances (PFAS), low-resolution MS/MS is the more commonly used and affordable approach for routine PFAS monitoring. Of note, perfluoropentanoic acid (PFPeA) and perfluorobutanoic acid (PFBA), two of the smaller carboxylic acid containing-PFAS, have only one major MS/MS transition, preventing the use of qualitative transitions for verification on low-resolution instrumentation. Recently our lab has observed widespread chemical interference in the quantitative ion channel for PFPeA (263 â†’ 219) and PFBA (213 â†’ 169) in numerous matrices. PFPeA interference was investigated using HRMS and putatively assigned as a diprotic unsaturated fatty acid (263.1288 Da) in shellfish and a separate interferent (13C isotope of 262.1087 Da) in hot cocoa, which had been previously described by the FDA. PFBA interference caused by saturated oxo-fatty acids, previously demonstrated in tissue, was also observed in liquid condensate from a residential air conditioning unit. Therefore, in support of PFAS analysis on low-resolution instrumentation, authors recommend several adjustments to analytical methods including altering liquid chromatography (LC) conditions as well as using matched internal standards to investigate and expressly confirm PFBA and PFPeA detections in both biological and environmental samples.

The placenta epigenome-brain axis: placental epigenomic and transcriptomic responses that preprogram cognitive impairment.

Aim: The placenta-brain axis reflects a developmental linkage where disrupted placental function is associated with impaired neurodevelopment later in life. Placental gene expression and the expression of epigenetic modifiers such as miRNAs may be tied to these impairments and are understudied. Materials & methods: The expression levels of mRNAs (n = 37,268) and their targeting miRNAs (n = 2083) were assessed within placentas collected from the ELGAN study cohort (n = 386). The ELGAN adolescents were assessed for neurocognitive function at age 10 and the association with placental mRNA/miRNAs was determined. Results: Placental mRNAs related to inflammatory and apoptotic processes are under miRNA control and associated with cognitive impairment at age 10. Conclusion: Findings highlight key placenta epigenome-brain relationships that support the developmental origins of health and disease hypothesis.

Children born extremely preterm are at increased risk for neurodevelopmental impairments such as cerebral palsy, intellectual disability and autism. The biological processes that lead to these impairments likely begin before birth and involve altered placental function. In this study, the authors analyzed placental genomic and epigenomic data from children who were born extremely preterm in relation to cognitive assessments at 10 years of age. They examined the differences between the expression of placental genes and molecules that influence the expression of placental genes, comparing children who had impaired cognition at 10 years with children who did not. The results demonstrated elevated expression levels of genes involved in inflammatory processes and molecules that control the expression of these genes within the placentas of children who had impaired cognition at age 10.

A rapid assessment bioaccumulation screening (RABS) study design for emerging per-and polyfluoroalkyl substances in mice exposed to industrially impacted surface water.

The shift away from PFOS and PFOA production in the past 20 years towards shorter chain and replacement PFAS has led to the environmental release of complex mixtures of emerging PFAS for which bioaccumulation potential and toxicology are largely unknown. The rate at which emerging PFAS can be prioritized for research in these complex mixtures is often limited by the lack of available chemical standards. We developed a study design that rapidly assesses which emerging PFAS in an environmentally derived mixture have the potential for mammalian bioaccumulation and thus prioritize these emerging chemicals for standard synthesis and toxicity testing. Surface water was collected at an impacted site downstream of an industrial fluorochemical manufacturing outfall and concentrated 100-fold via weak anion exchange, solid-phase extraction. The concentrated extract contained 13 previously identified emerging PFAS, including hexafluoropropylene oxide-dimer acid (HFPO-DA). BALB/c mice were orally dosed with surface water concentrate once a day for seven days. Twenty-four hours after the last dose, liver, serum, urine, and feces were collected and the emerging PFAS were semi-quantified based on peak area counts. Of the 13 emerging PFAS, Nafion byproduct-2 (Nafion BP2), Hydro-EVE, PFO4DA, and PFO5DoA had the largest increases in percent composition when comparing serum and liver to the dosing solution, suggesting that these PFAS may have the highest bioaccumulation potential. This finding supports other studies that detected bioaccumulation of the same four PFAS in human serum collected from communities with contaminated drinking water. In the future, the Rapid Assessment Bioaccumulation Screening (RABS) study design can be extended to other complex industrial chemical mixtures impacting surface water in order to better inform chemical prioritization for acquisition and in vitro/in vivo toxicity testing of the potential pollutants.

Understanding the dynamics of physiological changes, protein expression, and PFAS in wildlife.

Per- and polyfluoroalkyl substances (PFAS) accumulation and elimination in both wildlife and humans is largely attributed to PFAS interactions with proteins, including but not limited to organic anion transporters (OATs), fatty acid binding proteins (FABPs), and serum proteins such as albumin. In wildlife, changes in the biotic and abiotic environment (e.g. salinity, temperature, reproductive stage, and health status) often lead to dynamic and responsive physiological changes that alter the prevalence and location of many proteins, including PFAS-related proteins. Therefore, we hypothesize that if key PFAS-related proteins are impacted as a result of environmentally induced as well as biologically programmed physiological changes (e.g. reproduction), then PFAS that associate with those proteins will also be impacted. Changes in tissue distribution across tissues of PFAS due to these dynamics may have implications for wildlife studies where these chemicals are measured in biological matrices (e.g., serum, feathers, eggs). For example, failure to account for factors contributing to PFAS variability in a tissue may result in exposure misclassification as measured concentrations may not reflect average exposure levels. The goal of this review is to share general information with the PFAS research community on what biotic and abiotic changes might be important to consider when designing and interpreting a biomonitoring or an ecotoxicity based wildlife study. This review will also draw on parallels from the epidemiological discipline to improve study design in wildlife research. Overall, understanding these connections between biotic and abiotic environments, dynamic protein levels, PFAS levels measured in wildlife, and epidemiology serves to strengthen study design and study interpretation and thus strengthen conclusions derived from wildlife studies for years to come.

Pre-pregnancy BMI-associated miRNA and mRNA expression signatures in the placenta highlight a sexually-dimorphic response to maternal underweight status.

Pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and neonatal health outcomes, with differences in risk observed between sexes. Given that the placenta is a sexually dimorphic organ and critical regulator of development, examining differences in placental mRNA and miRNA expression in relation to pre-pregnancy BMI may provide insight into responses to maternal BMI in utero. Here, genome-wide mRNA and miRNA expression levels were assessed in the placentas of infants born extremely preterm. Differences in expression were evaluated according to pre-pregnancy BMI status (1) overall and (2) in male and female placentas separately. Overall, 719 mRNAs were differentially expressed in relation to underweight status. Unexpectedly, no genes were differentially expressed in relation to overweight or obese status. In male placentas, 572 mRNAs were associated with underweight status, with 503 (70%) overlapping genes identified overall. Notably, 43/572 (8%) of the mRNAs associated with underweight status in male placentas were also gene targets of two miRNAs (miR-4057 and miR-128-1-5p) associated with underweight status in male placentas. Pathways regulating placental nutrient metabolism and angiogenesis were among those enriched in mRNAs associated with underweight status in males. This study is among the first to highlight a sexually dimorphic response to low pre-pregnancy BMI in the placenta.

Comparing the Predictivity of Human Placental Gene, microRNA, and CpG Methylation Signatures in Relation to Perinatal Outcomes.

Molecular signatures are being increasingly integrated into predictive biology applications. However, there are limited studies comparing the overall predictivity of transcriptomic versus epigenomic signatures in relation to perinatal outcomes. This study set out to evaluate mRNA and microRNA (miRNA) expression and cytosine-guanine dinucleotide (CpG) methylation signatures in human placental tissues and relate these to perinatal outcomes known to influence maternal/fetal health; namely, birth weight, placenta weight, placental damage, and placental inflammation. The following hypotheses were tested: (1) different molecular signatures will demonstrate varying levels of predictivity towards perinatal outcomes, and (2) these signatures will show disruptions from an example exposure (ie, cadmium) known to elicit perinatal toxicity. Multi-omic placental profiles from 390 infants in the Extremely Low Gestational Age Newborns cohort were used to develop molecular signatures that predict each perinatal outcome. Epigenomic signatures (ie, miRNA and CpG methylation) consistently demonstrated the highest levels of predictivity, with model performance metrics including R2 (predicted vs observed) values of 0.36-0.57 for continuous outcomes and balanced accuracy values of 0.49-0.77 for categorical outcomes. Top-ranking predictors included miRNAs involved in injury and inflammation. To demonstrate the utility of these predictive signatures in screening of potentially harmful exogenous insults, top-ranking miRNA predictors were analyzed in a separate pregnancy cohort and related to cadmium. Key predictive miRNAs demonstrated altered expression in association with cadmium exposure, including miR-210, known to impact placental cell growth, blood vessel development, and fetal weight. These findings inform future predictive biology applications, where additional benefit will be gained by including epigenetic markers.

Identification of an Analytical Method Interference for Perfluorobutanoic Acid in Biological Samples.

The investigation of per- and polyfluorinated alkyl substances (PFAS) in environmental and biological samples relies on both high- and low-resolution mass spectrometry (MS) techniques. While high-resolution MS (HRMS) can be used for identification and quantification of novel compounds, low-resolution MS is the more commonly used and affordable approach for studies examining previously identified PFAS. Of note, perfluorobutanoic acid (PFBA) is one of the smaller PFAS observed in biological and environmental samples and has only one major MS/MS transition, preventing the use of qualitative transitions for verification. Recently, our laboratories undertook a targeted investigation of PFAS in the human placenta from high-risk pregnancies utilizing low-resolution, targeted MS/MS. Examination of placental samples revealed a widespread (n = 93/122 (76%)) chemical interferent in the quantitative ion channel for PFBA (213 → 169). PFBA concentrations were influenced by up to ∼3 ng/g. Therefore, additional chromatographic and HRMS/MS instrumentation was utilized to investigate the suspect peak and putatively assign the identity of the interfering compound as the saturated oxo-fatty acid (SOFA) 3-oxo-dodecanoic acid.

Placental programming, perinatal inflammation, and neurodevelopment impairment among those born extremely preterm.

Individuals born extremely preterm are at significant risk for impaired neurodevelopment. After discharge from the neonatal intensive care, associations between the child's well-being and factors in the home and social environment become increasingly apparent. Mothers' prenatal health and socioeconomic status are associated with neurodevelopmental outcomes, and emotional and behavioral problems. Research on early life risk factors and on mechanisms underlying inter-individual differences in neurodevelopment later in life can inform the design of personalized approaches to prevention. Here, we review early life predictors of inter-individual differences in later life neurodevelopment among those born extremely preterm. Among biological mechanisms that mediate relationships between early life predictors and later neurodevelopmental outcomes, we highlight evidence for disrupted placental processes and regulated at least in part via epigenetic mechanisms, as well as perinatal inflammation. In relation to these mechanisms, we focus on four prenatal antecedents of impaired neurodevelopment, namely, (1) fetal growth restriction, (2) maternal obesity, (3) placental microorganisms, and (4) socioeconomic adversity. In the future, this knowledge may inform efforts to detect and prevent adverse outcomes in infants born extremely preterm. IMPACT: This review highlights early life risk factors and mechanisms underlying inter-individual differences in neurodevelopment later in life. The review emphasizes research on early life risk factors (fetal growth restriction, maternal obesity, placental microorganisms, and socioeconomic adversity) and on mechanisms (disrupted placental processes and perinatal inflammation) underlying inter-individual differences in neurodevelopment later in life. The findings highlighted here may inform efforts to detect and prevent adverse outcomes in infants born extremely preterm.

A role for microRNAs in the epigenetic control of sexually dimorphic gene expression in the human placenta.

Aim: The contribution of miRNAs as epigenetic regulators of sexually dimorphic gene expression in the placenta is unknown. Materials & methods: 382 placentas from the extremely low gestational age newborns (ELGAN) cohort were evaluated for expression levels of 37,268 mRNAs and 2,102 miRNAs using genome-wide RNA-sequencing. Differential expression analysis was used to identify differences in the expression based on the sex of the fetus. Results: Sexually dimorphic expression was observed for 128 mRNAs and 59 miRNAs. A set of 25 miRNA master regulators was identified that likely contribute to the sexual dimorphic mRNA expression. Conclusion: These data highlight sex-dependent miRNA and mRNA patterning in the placenta and provide insight into a potential mechanism for observed sex differences in outcomes.

An assessment of serum-dependent impacts on intracellular accumulation and genomic response of per- and polyfluoroalkyl substances in a placental trophoblast model.

Per- and polyfluoroalkyl substances (PFAS), a class of environmental contaminants, have been detected in human placenta and cord blood. The mechanisms driving PFAS-induced effects on the placenta and adverse pregnancy outcomes are not well understood. This study investigated the impact of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and a replacement PFAS known as hexafluoropropylene oxide dimer acid (HFPO-DA, tradename GenX) on placental trophoblasts in vitro. Several key factors were addressed. First, PFAS levels in cell culture reagents at baseline were quantified. Second, the role of supplemental media serum in intracellular accumulation of PFAS in a human trophoblast (JEG3) cell line was established. Finally, the impact of PFAS on the expression of 96 genes involved in proper placental function in JEG3 cells was evaluated. The results revealed that serum-free media (SFM) contained no detectable PFAS. In contrast, fetal bovine serum-supplemented media (SSM) contained PFNA, PFUdA, PFTrDA, and 6:2 FTS, but these PFAS were not detected internally in cells. Intracellular accumulation following 24 hr treatments was significantly higher when cultured in SFM compared to SSM for PFOS and PFOA, but not HFPO-DA. Treatment with PFAS was associated with gene expression changes (n = 32) in pathways vital to placental function, including viability, syncytialization, inflammation, transport, and invasion/mesenchymal transition. Among the most robust PFAS-associated changes were those observed in the known apoptosis-related genes, BAD and BAX. These results suggest a complex relationship between PFAS, in vitro culture conditions, and altered expression of key genes necessary for proper placentation.

Placental genomic and epigenomic signatures associated with infant birth weight highlight mechanisms involved in collagen and growth factor signaling.

Birth weight (BW) represents an important clinical and toxicological measure, indicative of the overall health of the newborn as well as potential risk for later-in-life outcomes. BW can be influenced by endogenous and exogenous factors and is known to be heavily impacted in utero by the health and function of the placenta. An aspect that remains understudied is the influence of genomic and epigenomic programming within the placenta on infant BW. To address this gap, we set out to test the hypothesis that genes involved in critical placental cell signaling are associated with infant BW, and are likely regulated, in part, through epigenetic mechanisms based on microRNA (miRNA) mediation. This study leveraged a robust dataset based on 390 infants born at low gestational age (ranged 23-27 weeks) to evaluate genome-wide expression profiles of both mRNAs and miRNAs in placenta tissues and relate these to infant BW. A total of 254 mRNAs and 268 miRNAs were identified as associated with BW, the majority of which showed consistent associations across placentas derived from both males and females. BW-associated mRNAs were found to be enriched for important biological pathways, including glycoprotein VI (the major receptor for collagen), human growth, and hepatocyte growth factor signaling, a portion of which were predicted to be regulated by BW-associated miRNAs. These miRNA-regulated pathways highlight key mechanisms potentially linking endogenous/exogenous factors to changes in birth outcomes that may be deleterious to infant and later-in-life health.

Identifying Risk Factors for Levels of Per- and Polyfluoroalkyl Substances (PFAS) in the Placenta in a High-Risk Pregnancy Cohort in North Carolina.

Prenatal exposure to per- and polyfluoroalkyl substances (PFAS), a ubiquitous class of chemicals, is associated with adverse outcomes such as pre-eclampsia, low infant birth weight, and later-life adiposity. The objectives of this study were to examine PFAS levels in the placenta and identify sociodemographic risk factors in a high-risk pregnancy cohort (n = 122) in Chapel Hill, North Carolina. Of concern, PFOS, PFHxS, PFHpS, and PFUnA were detected above the reporting limit in 99, 75, 55, and 49% of placentas, respectively. Maternal race/ethnicity was associated with significant differences in PFUnA levels. While the data from this high-risk cohort did not provide evidence for an association with hypertensive disorders of pregnancy, fetal growth, or gestational age, the prevalence of detectable PFAS in the placenta suggests a need to biomonitor for exposure to PFAS during pregnancy. Future research should investigate factors underlying the differences in PFAS levels in association with a mother's race/ethnicity, as well as potential effects on pregnancy and child health.

Review of the environmental prenatal exposome and its relationship to maternal and fetal health.

Environmental chemicals comprise a major portion of the human exposome, with some shown to impact the health of susceptible populations, including pregnant women and developing fetuses. The placenta and cord blood serve as important biological windows into the maternal and fetal environments. In this article we review how environmental chemicals (defined here to include man-made chemicals [e.g., flame retardants, pesticides/herbicides, per- and polyfluoroalkyl substances], toxins, metals, and other xenobiotic compounds) contribute to the prenatal exposome and highlight future directions to advance this research field. Our findings from a survey of recent literature indicate the need to better understand the breadth of environmental chemicals that reach the placenta and cord blood, as well as the linkages between prenatal exposures, mechanisms of toxicity, and subsequent health outcomes. Research efforts tailored towards addressing these needs will provide a more comprehensive understanding of how environmental chemicals impact maternal and fetal health.

Differential metabolism of inorganic arsenic in mice from genetically diverse Collaborative Cross strains.

Mice have been frequently used to study the adverse effects of inorganic arsenic (iAs) exposure in laboratory settings. Like humans, mice metabolize iAs to monomethyl-As (MAs) and dimethyl-As (DMAs) metabolites. However, mice metabolize iAs more efficiently than humans, which may explain why some of the effects of iAs reported in humans have been difficult to reproduce in mice. In the present study, we searched for mouse strains in which iAs metabolism resembles that in humans. We examined iAs metabolism in male mice from 12 genetically diverse Collaborative Cross (CC) strains that were exposed to arsenite in drinking water (0.1 or 50 ppm) for 2 weeks. Concentrations of iAs and its metabolites were measured in urine and livers. Significant differences in total As concentration and in proportions of total As represented by iAs, MAs, and DMAs were observed between the strains. These differences were more pronounced in livers, particularly in mice exposed to 50 ppm iAs. In livers, large variations among the strains were found in percentage of iAs (15-48%), MAs (11-29%), and DMAs (29-66%). In contrast, DMAs represented 96-99% of total As in urine in all strains regardless of exposure. Notably, the percentages of As species in urine did not correlate with total As concentration in liver, suggesting that the urinary profiles were not representative of the internal exposure. In livers of mice exposed to 50 ppm, but not to 0.1 ppm iAs, As3mt expression correlated with percent of iAs and DMAs. No correlations were found between As3mt expression and the proportions of As species in urine regardless of exposure level. Although we did not find yet a CC strain in which proportions of As species in urine would match those reported in humans (typically 10-30% iAs, 10-20% MAs, 60-70% DMAs), CC strains characterized by low %DMAs in livers after exposure to 50 ppm iAs (suggesting inefficient iAs methylation) could be better models for studies aiming to reproduce effects of iAs described in humans.