The inhibitory mechanism of methylmercury on differentiation of human neuroblastoma cells.

Methylmercury (MeHg) is a ubiquitous environmental toxicant and shows neurotoxicity to central nerve system (CNS) or neuronal cells. It has been known that MeHg has more influence to developing or differentiating CNS/neuronal cells than adult or differentiated CNS/neuronal cells. This study examined the effect of MeHg on differentiation of human neuroblastoma SH-SY5Y cells induced by all-trans-retinoic acid (RA). MeHg caused the impairment of the RA-induced G(1/0) phase arrest; it was induced the reduction of G(1/0) phase and S phase arrest. Extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase C (PKC) are involved in the RA-mediated differentiation and cell cycle progression. Activation of ERK1/2 by RA was increased more in MeHg-treated differentiating cells, comparing with only RA-treated groups. Furthermore, in both cases of inhibition of ERK1/2 with PD98059 or inhibition of PKC with GF109203X, RA/MeHg-induced ERK1/2 phosphorylation was reduced and G(1/0) phase arrest was induced. Thus, it indicates that the neuronal differentiation with RA was mediated by the ERK1/2 and PKC related pathway and MeHg resulted in neurotoxic influences through the disturbance in steps of differentiation by this pathway. These results suggest that MeHg inhibits RA-induced differentiation in SH-SY5Y cells by a pathway dependent ERK1/2 and PKC.