[R21] Identifying PFAS-Induced Disruption of Placental Imprinting and Neurodevelopment Through Multi-Omic Negative Control Calibration

Ente: National Institute of Environmental Health Sciences

Scadenza: 2028-08-31

Importo max: $241,317

Paese: US

Descrizione

ABSTRACT While prenatal exposure to per- and polyfluoroalkyl substances (PFAS) is linked to altered neurodevelopmental outcomes including impaired social responsiveness, the mechanistic pathways connecting environmental exposure through placental genomic imprinting to offspring neurodevelopment remain poorly understood. Additionally, prioritizing potential causal links between environmental exposures and developmental outcomes in observational cohort studies is limited by unmeasured confounding, requiring improved statistical methods that leverage multi-omic data to distinguish true mediating pathways from spurious associations. PFAS are ubiquitous environmental contaminants detected in over 95% of pregnant women worldwide, with prenatal exposure associated with Social Responsiveness Scale deficits. The placenta serves as the critical interface mediating these effects through epigenetic mechanisms including genomic imprinting and alternative splicing that are particularly vulnerable to chemical exposures. We hypothesize that gestational PFAS exposure disrupts transcript-isoform imprinting in placental neurodevelopment-associated pathways, leading to altered offspring social responsiveness. This project leverages two birth cohorts with parent-offspring genotypes, maternal PFAS measurements, placental multi-omics data, and neurodevelopmental assessments (GUSTO, n=102; ELGAN, n=86). Aim 1 will characterize PFAS-associated changes to placental parent-of-origin isoform regulation using negative binomial generalized linear mixed models for expression data and Beta regression models for DNA methylation data. Cell-type deconvolution will identify vulnerable genomic regions across eight PFAS compounds. Aim 2 will develop and validate SCENIC, an R package implementing four causal inference approaches using Generative Adversarial Networks to address unmeasured confounding. We will then test whether PFAS-induced placental imprinting disruptions mediate effects on infant social responsiveness. This research addresses critical gaps by advancing beyond gene-level analyses to isoform-specific, cell-type-aware approaches while providing methodological innovations for molecular epidemiology and environmental health research. Expected outcomes include identification of 10-20 genes and 30-80 isoforms with significant PFAS × parent-of-origin interactions per compound, validation of mediation pathways, and a causal inference R package. This work will inform understanding of PFAS effects on genomic imprinting and guide targeted interventions during critical developmental windows. Istituzione: UNIVERSITY OF TX MD ANDERSON CAN CTR PI: Arjun Bhattacharya Progetto: 1R21ES039048-01

Settori: National Institute of Environmental Health Sciences

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