Piloting developmental PFAS exposure to identify gene-environment interactions in autism risk - The incidence of Autism Spectrum Disorder (ASD) is rapidly and inexplicably rising with 1 in 36 US children diagnosed in 2023, yet little is known about its etiology. ASD is debilitating and poses great societal and economic burdens, thus a critically important public health need is to understand its origins. However, this has been hindered by the heterogeneous presentation of the core behavioral domains in ASD, which include deficits in social communication, restricted/repetitive behavior and interests. Genetics account for only 30-40% of ASD heritability, suggesting that environmental stressors such as immune activation or pollutants, transferred via the mother may confer risk to offspring. Abnormal fetal brain development is regulated by the placenta and ASD has been associated with placental epigenetic dysfunction. Identification of placental gene biomarkers that are causally related to ASD-risk in offspring could help elucidate early pathogenesis and prediction of ASD. Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) or “Forever Chemicals”, found in ppm levels in drinking water, is suspected of elevating ASD risk through immune dysfunction. PFAS immunosuppressive effects may aggravate actions of other environmental stressors such as maternal immune activation (MIA). For example, viral infection during pregnancy can double the risk of ASD in offspring. Therefore, a critically important, but unmet need, is to understand how environmental “hits” during development may interact with genetic predisposition to exacerbate ASD risk using a placental-fetal model. During pregnancy, the common PFAS species, perfluorooctanesulfonic acid (PFOS) bioaccumulates in placenta and is transferred to fetal brain. Together, these data suggest that some environmental ASD risk factors could be avoided yet no experimental studies have investigated the ASD-relevant neurodevelopmental effects of PFOS exposure. Our long-term goal is to examine gene-environment (GxE) interactions at the placental-fetal interface and their consequences on fetal neurodevelopment and ASD-relevant behavior using loss- and gain-of function studies. As a first step the proposed studies will test the effects of developmental exposure to 2 PFAS species, PFOS and PFOA at 2 human-relevant doses (0.1 and 0.3 mg/kg/d) on ASD-like behavior phenotypes and accompanying brain transcriptomics using mass spectrometry, behavioral methods and transcriptomics. Using proinflammatory cytokine immunoassays, immune dysfunction profiles will also be examined and integrated with ASD-relevant phenotypes. Our findings will help identify neuroactive PFAS species at translational doses using maternal transfer in an environmental toxicant model of autism. Our transcriptomics data will inform about how relevant gene pathways in early fetal neurodevelopmental influence offspring ASD-like traits. This innovative, self- contained feasibility study is highly receptive to NIEHS’s areas of interest, “identify and validate biomarkers of susceptibility to exposures“ and “explore their interrelationships and their relevance to ASD risk and related phenotypes.”
