Investigations of methylmercury-induced alterations in neurogenesis

Methylmercury (MeHg) has been an environmental concern to public health and regulatory agencies for over 50 years because of its toxicity to the human nervous system. Its association with nervous system toxicity in adults and infants near Minamata Bay, Japan, in the 1950s initiated environmental health research inquiries that continue to this day. Observations of greater neurotoxicity with gestational compared with adult exposure suggest a unique susceptibility of the developing nervous system to MeHg. Despite extensive research conducted over the last half century, determination of definitive molecular mechanisms underlying the observed neurotoxic effects of MeHg have not been identified. This paper summarizes results of a series of experiments conducted to examine the effects of MeHg on neuroepithelial cell proliferation, a hypothesized mode of action for its selective effects on neurogenesis. Observed effects of MeHg on cell cycle entry and progression were associated with alterations in a variety of cell cycle regulatory molecules, including p21 signaling pathways. We place these studies in the context of other cellular responses involved in signal transduction, including oxidative stress, altered protein phosphorylation, and altered intracellular calcium homeostasis. Although existing information suggests that no single mechanism underlies the diverse array of effects associated with MeHg-induced developmental neurotoxicity, we demonstrate characteristic effects of MeHg on cell signaling that contribute to observed effects on cell proliferation. Experimentally derived cell cycle kinetic and cytotoxicity data allowed development of a biologically based dose-response model of MeHg-induced alterations in neurodevelopment, which can form the basis for information synthesis and hypothesis testing and for use in assessing risks from environmental exposures.