Prenatal 1-Nitropyrene Exposure Causes Autism-Like Behavior Partially by Altering DNA Hydroxymethylation in Developing Brain.

ABSTRACT

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by social communication disability and stereotypic behavior. This study aims to investigate the impact of prenatal exposure to 1-nitropyrene (1-NP), a key component of motor vehicle exhaust, on autism-like behaviors in a mouse model. Three-chamber test finds that prenatal 1-NP exposure causes autism-like behaviors during the weaning period. Patch clamp shows that inhibitory synaptic transmission is reduced in medial prefrontal cortex of 1-NP-exposed weaning pups. Immunofluorescence finds that prenatal 1-NP exposure reduces the number of prefrontal glutamate decarboxylase 67 (GAD67) positive interneurons in fetuses and weaning pups. Moreover, prenatal 1-NP exposure retards tangential migration of GAD67-positive interneurons and downregulates interneuron migration-related genes, such as Nrg1, Erbb4, and Sema3F, in fetal forebrain. Mechanistically, prenatal 1-NP exposure reduces hydroxymethylation of interneuron migration-related genes through inhibiting ten-eleven translocation (TET) activity in fetal forebrain. Supplement with alpha-ketoglutarate (α-KG), a cofactor of TET enzyme, reverses 1-NP-induced hypohydroxymethylation at specific sites of interneuron migration-related genes. Moreover, α-KG supplement alleviates 1-NP-induced migration retardation of interneurons in fetal forebrain. Finally, maternal α-KG supplement improves 1-NP-induced autism-like behaviors in weaning offspring. In conclusion, prenatal 1-NP exposure causes autism-like behavior partially by altering DNA hydroxymethylation of interneuron migration-related genes in developing brain.