Interactions of Polychlorinated Biphenyls and Their\nMetabolites with the Brain and Liver Transcriptome of Female Mice

Exposure to polychlorinated\nbiphenyls (PCBs) is linked to neurotoxic\neffects. This study aims to close knowledge gaps regarding the specific\nmodes of action of PCBs in female C57BL/6J mice (>6 weeks) orally\nexposed for 7 weeks to a human-relevant PCB mixture (MARBLES mix)\nat 0, 0.1, 1, and 6 mg/kg body weight/day. PCB and hydroxylated PCB\n(OH-PCBs) levels were quantified in the brain, liver, and serum; RNA\nsequencing was performed in the striatum, prefrontal cortex, and liver,\nand metabolomic analyses were performed in the striatum. Profiles\nof PCBs but not their hydroxylated metabolites were similar in all\ntissues. In the prefrontal cortex, PCB exposure activated the oxidative\nphosphorylation respiration pathways, while suppressing the axon guidance\npathway. PCB exposure significantly changed the expression of genes\nassociated with neurodevelopmental and neurodegenerative diseases\nin the striatum, impacting pathways like growth hormone synthesis\nand dendrite development. PCBs did not affect the striatal metabolome.\nIn contrast to the liver, which showed activation of metabolic processes\nfollowing PCB exposure and the induction of cytochrome P450 enzymes,\nthe expression of xenobiotic processing genes was not altered by PCB\nexposure in either brain region. Network analysis revealed complex\ninteractions between individual PCBs (e.g., PCB28 [2,4,4′-trichlorobiphenyl])\nand their hydroxylated metabolites and specific differentially expressed\ngenes (DEGs), underscoring the need to characterize the association\nbetween specific PCBs and DEGs. These findings enhance the understanding\nof PCB neurotoxic mechanisms and their potential implications for\nhuman health.