Autism Spectrum Disorder (ASD) affects approximately 1 in 31 children in the United States, with a strong male bias. ASD is characterized by impairments in social communication and interaction, as well as restricted/repetitive behaviors. Although the etiology of ASD remains unclear, growing evidence suggests that environmental factors contribute to ASD risk. Polyfluoroalkyl substances (PFAS), commonly referred to as “Forever chemicals,” represent a class of persistent environmental contaminants widely used in industrial and consumer products, including water-repellent textiles and firefighting foams. As a result, many PFAS species have contaminated drinking water and soil, with perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) being detected in approximately 95% of Americans. Epidemiological studies have associated PFAS exposure with endocrine disruption of thyroid hormones, which are critical for normal neurodevelopment and linked to ASD risk. However, experimental studies testing a causal relationship between developmental PFAS exposure and ASD-like behavioral outcomes are lacking. In this study, we tested the hypothesis that maternal exposure to PFOS or PFOA produces ASD-like behavioral phenotypes in mouse offspring. C57BL/6 mouse dams were exposed to one of five treatment groups: vehicle control, low- or high-dose PFOA or low- or high-dose PFOS (0.1 or 0.3 mg/kg) via infused cornflake treats throughout mating and gestation up to day of birth (P0). Offspring were weaned at P21 and behaviorally assessed using a battery of behavioral assays targeting core ASD-relevant domains, including exploration of familiar pup after a previous day exposure (social recognition memory test-SMRT) at P32, marble burying test (repetitive behavior) at P40, three-chamber apparatus (sociability) at P50, Open Field Test (exploratory locomotor activity) at P50, and Novel Object Recognition Test (NORT) (long-term non-social memory) at P60. Our results show that low-dose PFOA and high-dose PFOS prevented SRM in males whereas VEH/CON showed the typical reduction in exploration of stimulus mouse on Day 2 vs Day 1 (p< 0.0001). In females, low-dose PFOS females showed normal SRM as did VEH/CON (p< 0.01). Low- and high-dose PFOA exposure produced abnormal SRM in females. MB scores were significantly elevated in males exposed to high- but not low-dose PFOS relative to VEH/CON (p< 0.0001) whereas all female groups appeared normal. There were no group effects on sociability or exploratory locomotor behavior. VEH/CON males but not exposed males showed increased exploration of novel objects (p< 0.01). Collectively, these findings demonstrate that developmental exposure to PFOS and PFOA induced sex-dependent ASD-like behavioral phenotypes in mice and established a causal link between PFAS exposure and neurobehavioral reprogramming relevant to ASD. This model provides a critical experimental platform for future mechanistic studies examining how Forever chemicals may alter social neural circuits. Future LC/MS analysis on exposed offspring brain will help determine translational relevance of our experimental PFOS and PFOA exposure model. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Kozlova et al. (Fri,) studied this question.