2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits cell proliferation through arylhydrocarbon receptor-mediated G1 arrest in SK-N-SH human neuronal cells.

The neurotoxic mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has not been completely elucidated. In this study we investigated the possible role of cell cycle regulators and their dependence on arylhydrocarbon receptor (AhR) in the TCDD-mediated inhibition of cell proliferation using a human neuronal cell system. TCDD suppressed DNA synthesis of SK-N-SH human neuronal cells determined by [(3)H]thymidine incorporation which was significantly prevented either by pretreatment with alpha-naphthoflavone (alpha-NF), a partial AhR antagonist, or 8-methoxypsoralen (MOP), a binding inhibitor of activated AhR to dioxin response elements. Cell cycle analysis showed that TCDD induced a G(1) cell cycle arrest, which was also significantly prevented by pretreatment with alpha-NF and MOP. TCDD did not alter the expression of cyclin D, cyclin E, p21 and p53. However, TCDD induced an enhanced expression of p27 and a hypophosphorylation of pRb, which was prevented by alpha-NF and MOP. Combined, these results suggest that the TCDD-induced inhibition of neuronal cell proliferation may be due to the AhR-dependent G(1) arrest through an enhanced expression of p27 and a hypophosphorylation of pRB.