Preliminary evaluation of the mechanism underlying vulnerability/resistance to methylmercury toxicity by comparative gene expression profiling of rat primary cultured cerebrocortical and hippocampal neurons.

Methylmercury (MeHg), an environmentally toxic substance, causes site-specific neuronal cell death; while MeHg exposure causes death in cerebrocortical neurons, interestingly, it does not in hippocampal neurons, which are generally considered to be vulnerable to toxic substances. This phenomenon of site-specific neuronal cell death can be reproduced in animal experiments; however, the mechanism underlying the resistance of hippocampal neurons to MeHg toxicity has not been clarified. In this study, we comparatively analyzed the response to MeHg exposure in terms of viability and the expression characteristics of primary cultured cerebrocortical neurons and hippocampal neurons derived from fetal rat brain. Neuronal differentiated hippocampal neurons were more resistant to MeHg toxicity than cerebrocortical neurons, as indicated by a 2‒3 fold higher half-maximal inhibitory concentration (IC50; 3.3 μM vs. 1.2 μM), despite similar intracellular mercury concentrations in both neuronal cell types. Comprehensive RNA sequencing-based gene expression analysis of non-MeHg-exposed cells revealed that 80 out of 15,208 genes showed at least 10-fold higher expression in hippocampal neurons than in cerebrocortical neurons, whereas six genes showed at least 10-fold higher expression in cerebrocortical neurons than in hippocampal neurons. In particular, genes related to neuronal function, including those encoding transthyretin and brain-derived neurotrophic factor, showed approximately 50-fold higher expression in hippocampal neurons than in cerebrocortical neurons. In conclusion, the resistance of hippocampal neurons to MeHg toxicity may be related to the high expression of neuronal function-related proteins.