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

Abstract

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.

Systematic revelation of the protective effect and mechanism of Cordycep sinensis on diethylnitrosamine-induced rat hepatocellular carcinoma with proteomics

“…In addition, GRP75 and GRP78 which function as chaperone in protein folding, had no obvious alteration in volume. However, 2-DE oxyblot revealed that both GRP75 and GRP78 are highly carbonylated under DEN application and suggested a significant relationship between loss of function of chaperone proteins and the clinicopathological features of hepatoma [ 38 ].…”

Lead toxicity: a review

“…Heme precursors, such as aminolevulinic acid, have been found to build up due to their interference with lead, which may be directly or indirectly harmful to neurons (Fujita et al ., 2002 ). In a recent finding accumulation of organic lead in the liver was found to induce oxidative imbalance and protein impairment that may result in ER stress followed by liver injuries (Fang et al ., 2014 ). In another recent study the effect of lead exposure on C57BL/6J mice was observed.…”

Zinc ameliorates lead toxicity by reducing body Pb burden and restoring Pb-induced haematological and biochemical derangements

“…[56][57][58] Fang et al have also documented that accumulation of organic lead in the liver induced oxidative imbalance and protein impairment, which the authors suggested may result in liver injuries. 13 Raised liver enzymes may be due to the leakage of enzymes into the blood stream. It has been found that increased release of AST and ALT from the liver may be due to cellular degeneration and destruction of the liver cells, which gives an indication of the hepatotoxic effect of lead.…”

“…1 Apart from occupational exposure, which is the major cause of lead poisoning, 2,3 non-occupational exposure to lead include use of leaded gasoline, consumption of lead laden wine, 4 flaking of lead paint from old houses, 5,6 ingestion of lead contaminated food (including vegetable and fruits grown in lead contaminated soil) and water, accidental ingestion of lead contaminated soil and dust, 7 consumption of herbal and Ayurvedic and Chinese medicine and use of local cosmetics. [8][9][10][11][12] Lead toxicity affects virtually all the organs and system, [13][14][15] with its effects most devastating to the nervous system 14 , especially in children and pregnant women. 16 Long-term exposure to lead has been associated with some diseases including anaemia, hypertension, renal disease, diabetes mellitus, impaired fertility, just to mention but few 17,18 .…”