Evaluation of the hepatotoxic risk caused by lead acetate via skin exposure using a proteomic approach.

Lead compounds exhibit a high degree of cytotoxicity and carcinogenicity. We evaluated the impact of lead acetate on the liver by skin exposure as well as the changes in protein profiles reflecting pathogenic processes. Functional proteomic tools showed that the most meaningful protein changes were involved in protein folding, ER stress, and apoptosis in the presence of an organic lead compound. Treatment with lead acetate also elicits intracellular ROS levels as well as carbonyl modification of chaperone proteins, suggesting that lead might trigger the unfolded protein response due to oxidative stress. Lead application induced ER stress, as indicated by the promotion of GRP78 and by increased expression of the transcription factors ATF6, IRE1α, and PERK. Moreover, upregulation of GRP75 may participate in lead-caused hepatic cytotoxicity while abrogation of GRP75 appears to attenuate the inhibition of cell growth. Our findings demonstrate that accumulation of organic lead in the liver can induce oxidative imbalance and protein impairment that may result in ER stress followed by liver injuries. Hepatic proteome profiles delineate a finer picture of protein networks and metabolic pathways primarily involved in lead-initiated hepatic toxicity via skin exposure.