Prenatal low-dose MeHg exposure leads to proteomic and transcriptomic alterations consistent with neurodegenerative disease in the cerebellum of C57BL/6 mice

Methylmercury (MeHg) is a global pollutant that readily crosses the blood–brain barrier and placenta, posing significant risks to fetal neurodevelopment. While the cerebellum is a recognized target of MeHg toxicity in adults, the mechanisms underlying fetal exposure remain poorly defined. In this study, we investigated the neurotoxic effects of low-dose MeHg exposure (0.2 ppm via drinking water) on the cerebellums of prenatal C57BL/6 mice using integrated transcriptomic and proteomic analyses. Cerebellar tissues collected from postnatal day 90–120 (P90–120) mice (n = 3/group) were processed for RNA sequencing and proteomics analysis. Differentially expressed genes (DEGs) and proteins (DEPs) revealed significant changes in multiple pathways associated with neurodegeneration, including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Overlapping transcriptomic and proteomic findings identified potential underlying mechanisms such as chemical carcinogenesis driven by reactive oxygen species and retrograde endocannabinoid signaling, underscoring the central role of oxidative stress in MeHg-induced neurotoxicity. Collectively, these results indicate that prenatal MeHg exposure induces persistent molecular alterations consistent with neurodegenerative processes and synaptic dysfunction, despite the absence of overt behavioral changes at the time of sacrifice. The long-term consequences for delayed symptom onset and the potential contribution of these changes to the etiology of neurodevelopmental disorders warrant further investigation. Overall design: Pregnant C57BL/6 mice were dosed with 0 ppm or 0.2 ppm MeHg via drinking water starting from the first day of their pregnancy (E0) until birth (P0). The 0.2 ppm MeHg solution was prepared by a 1:5000 dilution of a stock solution of 4mM MeHg(II)Cl (cat#33553, Alfa Aesar) in drinking water. At sacrifice, the brains were dissected, and the cerebellum was isolated and immediately frozen with liquid nitrogen and stored at -80°C for analysis.