Long-chain perfluoroalkylether carboxylic acids PFO5DoA and PFO4DA alter glucose, bile acid, and thyroid hormone homeostasis in fetal rats from 5-day maternal oral exposure.

Chemical monitoring studies in North Carolina, USA and Shandong, China have reported detections of perfluoroalkylether carboxylic acids of increasing chain length with ether bonds between each fluorinated carbon. Despite detection there is limited hazard data available to inform risk assessment. Here, we exposed pregnant Sprague-Dawley rats to two of these compounds, perfluoro-3,5,7,9-butaoxadecanoic acid (PFO4DA) and perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA), from gestation days 18-22 across a series of doses (0.

Exploring maternal and developmental toxicity of perfluoroalkyl ether acids PFO4DA and PFO5DoA using hepatic transcriptomics and serum metabolomics.

Production of per- and polyfluoroalkyl substances (PFAS) has shifted from long-chain perfluoroalkyl acids to short-chain compounds and those with ether bonds in the carbon chain. Next-generation perfluoroalkylether PFAS include HFPO-DA ("GenX chemicals"), Nafion Byproducts, and the PFOx homologous series that includes perfluoro-3,5,7,9-butaoxadecanoic acid (PFO4DA) and perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA). PFO4DA and PFO5DoA have been detected in serum and/or tissues from humans and wildlife proximal to contamination point sources.

Combined screening and retroactive data mining for emerging perfluoroethers in wildlife and pets in the Cape Fear region of North Carolina.

The recent application of non-targeted analysis (NTA) techniques in environmental monitoring has revealed numerous novel fluorinated species in surface water, wildlife, and humans in the Cape Fear River (CFR) region of North Carolina. In this study, we have re-examined archived alligator, striped bass, horse, and dog serum as well as archived seabird tissue data from previously reported exposure studies in order to extend the panel of detected novel PFAS. In this study, the compounds CF-(OCF)-COOH, x = 6, 7, 8 (Abbreviated PFO6TeDA, PFO7HxDA, PFO8OcDA, respectively), and 6H-Perfluoro-3-oxa,4-methylhexanesulfonic acid (Nafion byproduct 6) were detected for the first time in environmental tissues even though these analytes were not previously detected in the CFR.

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).

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.

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).

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.

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 → 219) and PFBA (213 → 169) in numerous matrices.

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

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. 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).

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.

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.

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.

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.

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.

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

The contribution of miRNAs as epigenetic regulators of sexually dimorphic gene expression in the placenta is unknown. 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.

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.

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.

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 ( = 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.

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.

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.

Developing novel in vitro methods for the risk assessment of developmental and placental toxicants in the environment.

During pregnancy, the placenta is critical for the regulation of maternal homeostasis and fetal growth and development. Exposures to environmental chemicals during pregnancy can be detrimental to the health of the placenta and therefore adversely impact maternal and fetal health. Though research on placental-derived developmental toxicity is expanding, testing is limited by the resources required for traditional test methods based on whole animal experimentation.

Early life antecedents of positive child health among 10-year-old children born extremely preterm.

Background: To identify modifiable antecedents during pre-pregnancy and pregnancy windows associated with a positive child health at 10 years of age.

Methods: Data on 889 children enrolled in the Extremely Low Gestational Age Newborn (ELGAN) study in 2002-2004 were analyzed for associations between potentially modifiable maternal antecedents during pre-pregnancy and pregnancy time windows and a previously described positive child health index (PCHI) score at 10 years of age. Stratification by race was also investigated for associations with investigated antecedents.