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Marginalized populations experience disproportionate rates of preterm birth and early term birth. Exposure to per- and polyfluoroalkyl substances (PFAS) has been reported to reduce length of gestation, but the underlying mechanisms are unknown. In the present study, we characterized the molecular signatures of prenatal PFAS exposure and gestational age at birth outcomes in the newborn dried blood spot metabolome among 267 African American dyads in Atlanta, Georgia between 2016 and 2020. Pregnant people with higher serum perfluorooctanoic acid and perfluorohexane sulfonic acid concentrations had increased odds of an early birth. After false discovery rate correction, the effect of prenatal PFAS exposure on reduced length of gestation was associated with 8 metabolomic pathways and 52 metabolites in newborn dried blood spots, which suggested perturbed tissue neogenesis, neuroendocrine function, and redox homeostasis. These mechanisms explain how prenatal PFAS exposure gives rise to the leading cause of infant death in the United States. Mechanisms of the impact of PFAS (also known as forever chemicals) on adverse birth outcomes remain largely unknown. Here, authors identified tissue neogenesis, neuroendocrine function, and redox homeostasis as imprints of prenatal PFAS exposures and reduced gestational age in the newborn metabolome.

We evaluated associations among exposure to prenatal phthalate metabolites, perturbations of the newborn metabolome, and infant neurobehavioral functioning in mother-newborn pairs enrolled in the Atlanta African American Maternal-Child Cohort during 2016–2018. We quantified eight phthalate metabolites in prenatal urine samples collected between 8- and 14-weeks’ (visit 1; n  = 216) and 24- and 30-weeks’ gestation (visit 2; n  = 145) and metabolite features in newborn dried-blood spot samples collected at delivery. Associations between phthalate metabolite concentrations and metabolic feature intensities at both visits were examined using adjusted generalized linear models (MWAS). Then, an exploratory meet-in-the-middle (MITM) analysis was conducted in a subset with NICU Neonatal Neurobehavioral Scale (NNNS) scores (visit 1 n  = 81; visit 2 n  = 71). In both the MWAS and MITM, many of the confirmed metabolites are involved in tyrosine and tryptophan metabolism, including tryptophan, tyrosine, thyroxine, and serine. This analysis elucidates how prenatal phthalate exposure disrupts the newborn metabolome and infant neurobehavioral outcomes. Prenatal exposure to phthalates has been linked to metabolic and neurodevelopmental disruptions but the mechanisms remain unclear. Here, the authors show that prenatal phthalate exposure alters newborn metabolite profiles, particularly in tyrosine and tryptophan pathways, which are associated with infant neurobehavioral outcomes.

Background: Per- and polyfluoroalkyl substances (PFASs) including perfluorooctanoic acid (PFOA) are ubiquitous environmental contaminants. Prior analysis in the large “C8 Health Project” population defined abnormal alanine aminotransferase (ALT) with statistically derived cutoffs (>45 IU/L in men, >34 IU/L in women). Objective: To explore the degree to which PFOA was associated with modern, clinically predictive ALT biomarker cutoffs in obese and nonobese participants, excluding those with diagnosed liver disease. Methods: We reevaluated the relationship of serum PFOA to abnormal ALT using predictive cutoff recommendations including those of the American College of Gastroenterology (ACG). Evaluations modeled lifetime cumulative exposure and measured internal PFOA exposure. Results: ACG cutoff values (≥34 IU/L for males, ≥25 IU/L for females) classified 30% of males (3815/12,672) and 21% of females (3359/15,788) above ALT cutoff values. Odds ratios (OR) for above cutoff values were consistently associated with modeled cumulative and measured serum PFOA. Linear trends were highly significant. ORs by quintile showed near monotonic increases. Trends were stronger for the overweight and obese. However, all weight classes were affected. Conclusion: Predictive cutoffs increase the OR for abnormal ALT results. Obesity increases ORs, yet association with abnormal ALT pertains to all weight classes. The results are discussed in context of current knowledge about the health implications of PFOA hepatotoxicity.

Polybrominated biphenyls (PBB) and polychlorinated biphenyls (PCB) are persistent organic pollutants with potential endocrine-disrupting effects linked to adverse health outcomes. In this study, we utilize high-resolution metabolomics (HRM) to identify internal exposure and biological responses underlying PCB and multigenerational PBB exposure for participants enrolled in the Michigan PBB Registry. HRM profiling was conducted on plasma samples collected from 2013 to 2014 from a subset of participants enrolled in the Michigan PBB Registry, including 369 directly exposed individuals (F0) who were alive when PBB mixtures were accidentally introduced into the food chain and 129 participants exposed to PBB or through breastfeeding, if applicable (F1). Metabolome-wide association studies were performed for PBB-153 separately for each generation and (PCB-118, PCB-138, PCB-153, and PCB-180) in the two generations combined, as both had direct PCB exposure. Metabolite and metabolic pathway alterations were evaluated following a well-established untargeted HRM workflow. Mean levels were [standard deviation (SD): 13.9] for PBB-153 and (SD: 0.788) for . Sixty-two and 26 metabolic features were significantly associated with PBB-153 in F0 and F1 [false discovery rate (FDR) ], respectively. There were 2,861 features associated with (FDR ). Metabolic pathway enrichment analysis using a bioinformatics tool revealed perturbations associated with in numerous oxidative stress and inflammation pathways (e.g., carnitine shuttle, glycosphingolipid, and vitamin B9 metabolism). Metabolic perturbations associated with PBB-153 in F0 were related to oxidative stress (e.g., pentose phosphate and vitamin C metabolism) and in F1 were related to energy production (e.g., pyrimidine, amino sugars, and lysine metabolism). Using authentic chemical standards, we confirmed the chemical identity of 29 metabolites associated with levels (level 1 evidence). Our results demonstrate that serum PBB-153 is associated with alterations in inflammation and oxidative stress-related pathways, which differed when stratified by generation. We also found that was associated with the downregulation of important neurotransmitters, serotonin, and 4-aminobutanoate. These findings provide novel insights for future investigations of molecular mechanisms underlying PBB and PCB exposure on health. https://doi.org/10.1289/EHP12657.

Longitudinal trends in per- and polyfluoroalkyl substances (PFAS) serum concentrations across pregnancy have not been thoroughly examined, despite evidence linking prenatal PFAS exposures with adverse birth outcomes. We sought to characterize longitudinal PFAS concentrations across pregnancy and to examine the maternal-fetal transfer ratio among participants in a study of risk and protective factors for adverse birth outcomes among African Americans. In the Atlanta African American Maternal-Child cohort (2014-2020), we quantified serum concentrations of four PFAS in 376 participants and an additional eight PFAS in a subset of 301 participants during early (8-14 weeks gestation) and late pregnancy (24-30 weeks gestation). Among these, PFAS concentrations were also measured among 199 newborns with available dried blood spot (DBS) samples. We characterized the patterns, variability, and associations in PFAS concentrations at different time points across pregnancy using intraclass correlation coefficients (ICCs), maternal-newborn pairs transfer ratios, linear mixed effect models, and multivariable linear regression, adjusting for socioeconomic and prenatal predictors. Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) were detected in of maternal samples, with PFHxS and PFOS having the highest median concentrations. We observed high variability in PFAS concentrations across pregnancy time points ( ). All median PFAS concentrations increased from early to late pregnancy, except for PFOA and N-methyl perfluorooctane sulfonamido acetic acid (NMFOSAA), which decreased [paired -test for all PFAS except for PFOA and perfluorobutane sulfonic acid (PFBS)]. Prenatal serum PFAS were weakly to moderately correlated with newborn DBS PFAS ( ). The median maternal-fetal PFAS transfer ratio was lower for PFAS with longer carbon chains. After adjusting for socioeconomic and prenatal predictors, in linear mixed effect models, the adjusted mean PFAS concentrations significantly increased during pregnancy, except for PFOA. In multivariable linear regression, PFAS concentrations in early pregnancy significantly predicted the PFAS concentrations in late pregnancy and in newborns. We found that the concentrations of most PFAS increased during pregnancy, and the magnitude of variability differed by individual PFAS. Future studies are needed to understand the influence of within-person PFAS variability during and after pregnancy on birth outcomes. https://doi.org/10.1289/EHP14334.

BackgroundAfrican Americans (AAs) experience higher rates of preterm birth and fetal growth restriction relative to other pregnant populations. Differential in utero exposure to environmental chemicals may partially explain these health disparities, as AAs are disproportionately exposed to environmental hazards.ObjectiveWe examined the individual and mixture effects of non-persistent chemicals and persistent organic pollutants (POPs) on gestational age at birth and birthweight for gestational age z-scores within a prospective cohort of pregnant AAs.MethodsFirst-trimester serum and urine samples obtained from participants within the Atlanta African American Maternal-Child cohort were analyzed for 43 environmental chemicals, including per-and polyfluoroalkyl substances (PFAS), polybrominated diphenyl ethers (PBDEs), organochlorine pesticides, pyrethroid insecticides, phthalates, bisphenol A, nicotine, and the primary metabolite of delta-9-tetrahydrocannabinol. Linear regression was used to estimate individual associations between chemicals and gestational age and birthweight z-scores (N ranging from 107 to 523). Mixture associations were estimated using quantile g-computation, principal component (PC) analyses, and hierarchical Bayesian kernel machine regression among complete cases (N = 86).ResultsUsing quantile g-computation, increasing all chemical exposures by one quantile was modestly associated with a reduction in gestational age (mean change per quartile increase = −0.47, 95% CI = −1.56, 0.61) and birthweight z-scores (mean change per quartile increase = −0.49, 95% CI = −1.14, 0.15). All PCs were associated with a reduction in birthweight z-scores; associations were greatest in magnitude for the two PCs reflecting exposure to combined tobacco, insecticides, PBDEs, and phthalates. In single pollutant models, we observed inconsistent and largely non-significant associations.SignifanceWe conducted multiple targeted exposure assessment methods to quantify levels of environmental chemicals and leveraged mixture methods to quantify their joint effects on gestational age and birthweight z-scores. Our findings suggest that prenatal exposure to multiple classes of persistent and non-persistent chemicals is associated with reduced gestational age and birthweight z-scores in AAs.ImpactAfrican Americans (AAs) experience higher rates of preterm birth and fetal growth restriction relative to other pregnant populations. Differential in utero exposure to environmental chemicals may partially explain these health disparities, as AAs are disproportionately exposed to environmental hazards. In the present study, we analyzed serum and urine samples for levels of 43 environmental chemicals. We used quantile g-computation, principal component analysis, and BKMR to assess associations between chemical exposure mixtures and adverse birth outcomes. Our findings suggest that prenatal exposure to multiple classes of chemicals is associated with reduced birthweight z-scores, a proxy for fetal growth, in AAs.

BACKGROUND: Longitudinal trends in per- and polyfluoroalkyl substances (PFAS) serum concentrations across pregnancy have not been thoroughly examined, despite evidence linking prenatal PFAS exposures with adverse birth outcomes. OBJECTIVES: We sought to characterize longitudinal PFAS concentrations across pregnancy and to examine the maternal-fetal transfer ratio among participants in a study of risk and protective factors for adverse birth outcomes among African Americans. METHODS: In the Atlanta African American Maternal-Child cohort (2014-2020), we quantified serum concentrations of four PFAS in 376 participants and an additional eight PFAS in a subset of 301 participants during early (8-14 weeks gestation) and late pregnancy (24-30 weeks gestation). Among these, PFAS concentrations were also measured among 199 newborns with available dried blood spot (DBS) samples. We characterized the patterns, variability, and associations in PFAS concentrations at different time points across pregnancy using intraclass correlation coefficients (ICCs), maternal-newborn pairs transfer ratios, linear mixed effect models, and multivariable linear regression, adjusting for socioeconomic and prenatal predictors. RESULTS: Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) were detected in >95% of maternal samples, with PFHxS and PFOS having the highest median concentrations. We observed high variability in PFAS concentrations across pregnancy time points (ICC = 0:03-0:59). All median PFAS concentrations increased from early to late pregnancy, except for PFOA and N-methyl perfluorooctane sulfonamido acetic acid (NMFOSAA), which decreased [paired t-test for all PFAS p <0:05 except for PFOA and perfluorobutane sulfonic acid (PFBS)]. Prenatal serum PFAS were weakly to moderately correlated with newborn DBS PFAS (--0:05 < rho <0:49). The median maternal-fetal PFAS transfer ratio was lower for PFAS with longer carbon chains. After adjusting for socioeconomic and prenatal predictors, in linear mixed effect models, the adjusted mean PFAS concentrations significantly increased during pregnancy, except for PFOA. In multivariable linear regression, PFAS concentrations in early pregnancy significantly predicted the PFAS concentrations in late pregnancy and in newborns. DISCUSSION: We found that the concentrations of most PFAS increased during pregnancy, and the magnitude of variability differed by individual PFAS. Future studies are needed to understand the influence of within-person PFAS variability during and after pregnancy on birth outcomes.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and neuropathological hallmarks. Despite extensive research, the molecular mechanisms linking metabolic dysregulation to AD neuropathology remain poorly understood. Metabolomics, a powerful tool for profiling small molecules, provides an opportunity to identify metabolic signatures and pathways implicated in disease progression. To address this gap, we conducted a comprehensive high-resolution brain metabolomics study, profiling metabolic perturbations associated with AD neuropathology. Using untargeted high-resolution metabolomics, we analyzed 162 frontal cortex samples from the Emory Goizueta Alzheimer's Disease Research Center brain bank with comprehensive neuropathological evaluations, including Braak stage, CERAD, and ABC scores. We conducted a metabolome-wide association study of AD neuropathology adjusting for confounders and multiple testing (FDR 5%). Pathway enrichment analysis was performed to uncover biological processes implicated in AD, and chemical annotation confirmed key metabolites with Level 1 evidence. We also examined potential effects of APOE ε4 genotype in modifying the associations between significant metabolic features and AD neuropathology markers. Our analysis identified 155 metabolic features, and 36 metabolic pathways significantly associated with the AD neuropathology markers, spanning ten metabolic classes such as energy metabolism, nucleotide metabolism, and amino acid metabolism. ABC score was linked to the largest number of pathways, while Braak stage and CERAD exhibited distinct metabolic associations, including nucleotide metabolism with tau pathology and fatty acid-related pathways with neuritic plaque deposition. Further, 18 unique metabolites were confirmed with level 1 evidence, implicating their involvement in amino acid metabolism, lipid metabolism, carbohydrate metabolism, nucleotide metabolism, and metabolism of cofactors and vitamins in AD neuropathology. Genetic variability influenced these associations, with non-carriers of the APOE ε4 allele showing stronger perturbations in metabolites including glucose, mannose, myo-inositol, and adenosine 5'-diphosphoribose. This study demonstrates the potential of high-resolution metabolomic profiling in brain tissues to elucidate molecular mechanisms underlying AD pathology. Our findings provide critical insights into metabolic dysregulation in AD and its interplay with genetic factors. Future longitudinal studies are needed to validate these findings and explore the functional significance of the identified metabolites in AD progression.

Background Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and neuropathological hallmarks. Despite extensive research, the molecular mechanisms linking metabolic dysregulation to AD neuropathology remain poorly understood. Metabolomics, a powerful tool for profiling small molecules, provides an opportunity to identify metabolic signatures and pathways implicated in disease progression. To address this gap, we conducted a comprehensive high‐resolution brain metabolomics study, profiling metabolic perturbations associated with AD neuropathology. Method Using untargeted high‐resolution metabolomics, we analyzed 162 frontal cortex samples from the Emory Goizueta Alzheimer's Disease Research Center brain bank with comprehensive neuropathological evaluations, including Braak stage, CERAD, and ABC scores. We conducted a metabolome‐wide association study of AD neuropathology adjusting for confounders and multiple testing (FDR 5%). Pathway enrichment analysis was performed to uncover biological processes implicated in AD, and chemical annotation confirmed key metabolites with Level 1 evidence. We also examined potential effects of APOE ε4 genotype in modifying the associations between significant metabolic features and AD neuropathology markers. Results Our analysis identified 155 metabolic features, and 36 metabolic pathways significantly associated with the AD neuropathology markers, spanning ten metabolic classes such as energy metabolism, nucleotide metabolism, and amino acid metabolism. ABC score was linked to the largest number of pathways, while Braak stage and CERAD exhibited distinct metabolic associations, including nucleotide metabolism with tau pathology and fatty acid‐related pathways with neuritic plaque deposition. Further, 18 unique metabolites were confirmed with level 1 evidence, implicating their involvement in amino acid metabolism, lipid metabolism, carbohydrate metabolism, nucleotide metabolism, and metabolism of cofactors and vitamins in AD neuropathology. Genetic variability influenced these associations, with non‐carriers of the APOE ε4 allele showing stronger perturbations in metabolites including glucose, mannose, myo‐inositol, and adenosine 5'‐diphosphoribose. Conclusion This study demonstrates the potential of high‐resolution metabolomic profiling in brain tissues to elucidate molecular mechanisms underlying AD pathology. Our findings provide critical insights into metabolic dysregulation in AD and its interplay with genetic factors. Future longitudinal studies are needed to validate these findings and explore the functional significance of the identified metabolites in AD progression.

INTRODUCTION This study aimed to identify specific biological pathways and molecules involved in Alzheimer's disease (AD) neuropathology. METHODS We conducted cutting‐edge high‐resolution metabolomics profiling of 162 human frontal cortex samples from the Emory Alzheimer's Disease Research Center (ADRC) brain bank with comprehensive neuropathological evaluations. RESULTS We identified 155 unique metabolic features and 36 pathways associated with three well‐established AD neuropathology markers. Of these, 18 novel metabolites were confirmed with level 1 evidence, implicating their involvement in amino acid metabolism, lipid metabolism, carbohydrate metabolism, nucleotide metabolism, and metabolism of cofactors and vitamins in AD neuropathology. Genetic variability influenced these associations, with non‐carriers of the apolipoprotein E (APOE) ε4 allele showing stronger perturbations in metabolites including glucose and adenosine 5′‐diphosphoribose. DISCUSSION This study demonstrates the potential of high‐resolution metabolomic profiling in brain tissues to elucidate molecular mechanisms underlying AD pathology. Our findings provide critical insights into metabolic dysregulation in AD and its interplay with genetic factors. Highlights This is one of the largest untargeted metabolomics studies of human brain tissue. 155 metabolic features, and 36 metabolic pathways were linked to Alzheimer's disease (AD) neuropathology. Of these, 18 unique metabolites were confirmed with level 1 evidence. Glucose and adenosine 5′‐diphosphoribose identified as key metabolic alterations in AD.