Gestational exposure to fenvalerate induces attention-deficit hyperactivity disorder-like behaviors partially through altered DNA hydroxymethylation in the fetal midbrain of weaning offspring

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Fenvalerate (FEN) is a typical pyrethroid pesticide known for its developmental toxicity. This study aimed to evaluate the effects of gestational FEN exposure on attention-deficit hyperactivity disorder (ADHD)-like behaviors in weaning offspring. Pregnant mice were administered FEN daily via oral gavage throughout pregnancy. ADHD-like behaviors were assessed in weaning offspring of FEN-exposed mothers using the open-field test (OFT) and Làt maze test (LMT). Gestational FEN exposure reduced dopamine (DA) content in the striatum of weaning offspring. Further analyses revealed decreased tyrosine hydroxylase (TH), the rate-limiting enzyme in DA synthesis, in the midbrains of both fetal and weaning pups. Mechanistically, FEN exposure reduced 5-hydroxymethylcytosine (5hmC) content in CpG-rich regions and specific sites within the TH gene in the fetal midbrain. Moreover, the activity of ten-eleven translocation (TET) enzymes was diminished in the fetal midbrain following FEN exposure. Supplementation with ascorbic acid (AA), a cofactor for TET enzymes, alleviated the FEN-induced reduction in 5hmC content in CpG-rich regions of TH gene in the fetal midbrain. AA supplementation also reversed the FEN-induced downregulation of midbrain TH expression and striatal DA levels in weaning offspring. Furthermore, AA supplementation rescued the FEN-induced ADHD-like behaviors in weaning offspring. These findings indicate that gestational FEN exposure induces ADHD-like behaviors in weaning offspring, partly by modifying the epigenetic regulation of DA synthesis. ● Gestational FEN exposure induces ADHD-like behaviors in weaning offspring. ● Gestational FEN exposure reduces dopamine content in the striatum of weaning offspring. ● Gestational FEN exposure reduces 5hmC levels of TH gene in the fetal midbrain. ● AA reveres gestational FEN-induced epigenetic reprogramming of TH gene in the fetal midbrain. ● AA alleviates gestational FEN-induced ADHD-like behaviors in weaning offspring.