Early-Life Arsenic Exposure Induces Histone H3K9 Methylation Causing PANoptosis and Neurodevelopmental Impairments in Offspring

Arsenic exposure is well-established to cause neurotoxicity, but its underlying molecular mechanisms remain unclear. This study investigates the effects of early-life arsenic exposure on the nervous system of offspring. Female mice were exposed to NaAsO₂, and alterations in learning, memory, and hippocampal lesions in offspring were assessed. Transcriptome analysis, protein interaction studies, and cellular experiments were integrated to identify key regulatory factors in arsenic-induced neurotoxicity. Arsenic interacts with HUWE1, significantly downregulating its protein expression. HUWE1 inhibition enhances GPX8 stability by reducing its ubiquitination. GPX8 disrupts histone epigenetic modifications by promoting GSH synthesis and arsenic methylation, leading to elevated H3K9 levels. HUWE1 also interacts with KDM3A, and its inhibition reduces KDM3A-mediated H3K9me1/me2 demethylation, amplifying H3K9me2-mediated transcriptional repression of LARS2 and triggering PANoptosis. This study provides novel molecular insights into arsenic-induced neurotoxicity and highlights potential therapeutic targets to mitigate arsenic-related nervous system damage.