Perinatal exposure to the autism-linked metabolite p-Cresol has limited impact on early development in mice but lasting effects on adult social behavior

Environmental exposures during pregnancy are increasingly recognized as significant risk factors for the offspring health. Perinatal exposure to environmental toxins, including p-Cresol, may disrupt essential physiological processes during critical developmental windows. The perinatal period is particularly critical for neurodevelopment, making the brain particularly vulnerable to external toxins that can impair neural circuitry and increase the risk of behavioral and neuropsychiatric disorders later in life. p-Cresol, a microbial metabolite produced by the human microbiota and through the bacterial decomposition of organic matter, is also released in exhaust fumes and widely used in chemical manufacturing. Elevated levels of p-Cresol have been consistently observed in patients with autism spectrum disorders (ASD), yet, its developmental toxicity and its impact on ASD-related behaviors remain to be determined. In this study, we exposed pregnant mice (C57BL/6J) to p-Cresol via drinking water from mid-gestation, through lactation, and until weaning, mimicking potential patterns of human exposure during pregnancy and early infancy. Our findings indicated that while perinatal p-Cresol exposure did not affect gestational outcomes, postnatal growth, developmental milestones, or sensorimotor reflexes, it resulted in marked social deficits and stereotyped behaviors in adult males and females offspring-which are core behavioral phenotypes associated with ASD. These results suggest that p-Cresol exposure selectively induces ASD-like behaviors, without broadly impairing early development. Our findings emphasize the need for future epidemiological studies to quantify p-Cresol exposure during pregnancy and early childhood, and to evaluate its potential association with social behavior impairments in children. This research provides a foundation for understanding how environmental factors, such as p-Cresol, may contribute to social impairments and neurodevelopmental disorders in the broader population.