Abstract
The developing nervous system is highly susceptible to methylmercury (MeHg), a widespread environmental neurotoxic contaminant. A wide range of morphological and functional outcomes have been described; however, there are still open questions regarding the mechanisms behind the developmental neurotoxic effects induced by low-level exposure. In the present study, we have examined the effects of nanomolar concentrations of MeHg on primary fetal human progenitor cells (hNPCs) with special focus on the role played by developmental stage and sex on the neurotoxic outcome. We found that neurospheres derived from earlier gestational time points exhibit higher susceptibility to MeHg, as they undergo apoptosis at a much lower dose (25 nM) as compared to neurospheres established from older fetuses (100 nM). At subapoptotic concentrations (10 nM), MeHg inhibited neuronal differentiation and maturation of hNPCs, as shown by a reduced number of Tuj1-positive cells and a visible reduction in neurite extension and cell migration, associated with a misregulation of Notch1 and BDNF signaling pathways. Interestingly, cells derived from male fetuses showed more severe alterations of neuronal morphology as compared to cells from females, indicating that the MeHg-induced impairment of neurite extension and cell migration is sex-dependent. Accordingly, the expression of the CDKL5 gene, a major factor regulating neurite outgrowth, was significantly more downregulated in male-derived cells. Altogether, gestational age and sex appear to be critical factors influencing in vitro hNPC sensitivity to low levels of MeHg.
Highlights
Methylmercury (MeHg) is a widespread environmental contaminant well known to be harmful during nervous system development
To further investigate the mechanisms involved in low doses of MeHg neurotoxicity, we examined putative sexrelated differences in the susceptibility to MeHg in primary human progenitor cells, with special focus on neuronal differentiation and maturation
We show that the cytotoxicity of low doses of MeHg in human neurospheres is influenced by gestational age and that subapoptotic concentrations of MeHg impair neuronal maturation in a sex-dependent manner
Summary
Methylmercury (MeHg) is a widespread environmental contaminant well known to be harmful during nervous system development. We have found that rat embryonic NPCs exposed to very low concentrations of MeHg undergo alterations in proliferation capacity and increased susceptibility to oxidative stress and that these changes are heritable as they are present in daughter cells never directly exposed to the neurotoxicant (Bose et al 2012). These cellular alterations are accompanied by changes in DNA methylation, suggesting the involvement of epigenetic mechanisms (Bose et al 2012). We found that male mice exposed to low levels of MeHg in utero exhibited reduced hippocampal neurogenesis even as adults and had fewer granule neurons in the dentate gyrus (Onishchenko et al 2008)
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