Genotoxicity and fibrosis in human hepatocytes in vitro from exposure to low doses of PBDE-47, arsenic, or both chemicals

Abstract

Improper disposal and recycling of electronic waste (e-waste) has been shown to cause extensive environmental pollution and human health effects. Among the pollutants, 2,2′,4,4’ Tetrabromodiphenyl Ether (PBDE-47) and arsenic are highly prevalent. This study aimed to investigate genotoxic and fibrosis effects, and their mechanistic relationships from exposure to PBDE-47, arsenic, or both chemicals in a human hepatocyte epithelial cell line (THLE-2). Non-cytotoxic concentrations of 5 μM PBDE-47 (2848 ppb), 0.5 μM arsenite (37.46 ppb), or co-exposure to both were selected and cells were exposed for 7 days. The co-exposure increased the effect of lipid peroxidation (MDA and 4-HNE) and the expression of inflammatory genes (CXCL6, CXCL8, and TGF-β1) over that of PBDE-47 or arsenite alone. Furthermore, the co-exposure significantly increased the level of mutagenic DNA adducts including MDA-derived DNA adducts (Pyrimido[1,2-a]purin-10(3H)-one, M1dG), 8-hydroxydeoxyguanosine (8-OHdG) and 8-nitroguanine; but decreased mRNA expression of an antioxidant defense regulator (NFE2L2) and DNA repair genes (hOGG1 and XRCC1). Regarding biological effects, the co-exposure increased cell migration, a hallmark of epithelial-mesenchymal transition (EMT); down-regulated the epithelial expression (E-cadherin); up-regulated mesenchymal expression (Vimentin); and promoted fibrosis expression (up-regulated ACTA2, FSP-1, and COL1A1). Collectively, these findings indicate that the co-exposure significantly induced a cascade of toxicological effects of overexposure to individual chemicals. The observed genotoxicity, abnormal gene expression, and fibrosis in hepatocytes indicate mechanisms and potentially further increase of health hazards than currently recognized in populations exposed to e-waste chemicals.