Left BLP to dmPFC circuit dysfunction underlies autism-like behaviors induced by prenatal and lactational Bisphenol S exposure.

Abstract

Environmental factors are increasingly implicated in autism spectrum disorder (ASD), and this study investigated whether bisphenol S (BPS), a widely used endocrine disruptor, induces autism-like phenotypes using mouse and neuronal models. Prenatal and lactational BPS exposure induced male-biased autism-like behaviors, including impaired sociability, increased repetitive behaviors, and anxiety-related alterations. These behavioral deficits were accompanied by prefrontal BPS accumulation, reduced regional homogeneity and c-Fos-positive neuronal activation in the left dorsomedial prefrontal cortex (dmPFC), and persistent synaptic abnormalities. Chemogenetic manipulation demonstrated that dmPFC activity is critical for the core social-deficit domain of BPS-induced autism-like behaviors, and that dmPFC activation alleviated these deficits. Further investigation via rs-fMRI and whole-brain monosynaptic retrograde tracing revealed weakened functional and anatomical connectivity between the left posterior basolateral amygdaloid nucleus (BLP) and dmPFC. This was associated with reduced CaMKIIα-positive excitatory neuronal phenotype and altered excitatory/inhibitory (E/I) marker profiles in the left BLP. Targeted activation of excitatory BLP-dmPFC projections ameliorated the core social deficits within BPS-induced autism-like behaviors. Collectively, our findings indicate that prenatal and lactational BPS exposure induces autism-like behaviors by disrupting the left BLP-dmPFC circuit, accompanied by altered E/I marker profiles and synaptic abnormalities. These findings establish a neural circuit basis for BPS-related neurodevelopmental toxicity.