Mitogen-activated Protein Kinase Signaling and Its Association with Oxidative Stress and Apoptosis in Lead-exposed Hepatocytes

Lead toxicity has become a serious public health concern all over the world. Previous studies have shown that lead induces biochemical and structural changes in liver. However, although lead is known to alter liver functions, the underlying molecular mechanisms of hepatotoxicity are not yet clear. We hypothesized that a correlation exists between oxidative stress, apoptosis and mitogen-activated protein kinases (MAPKs) in lead-exposed liver. Wistar rats were treated with 0, 0.5%, and 1% lead acetate for 3d, 14d, and 35d and sacrificed the next day. On 4d, oxidative stress and apoptosis were correlated with downregulated expressions of ERK1/2 and p38-MAPKα/β, and upregulated expressions of JNK1/3 in males. In females, the correlation was with downregulated expressions of ERK1/2 and upregulated expressions of p38-MAPKα/β and JNK1/3. On 15d, the correlation was observed with upregulated expressions of p38-MAPKα/β in males and downregulated expressions of p38-MAPKα/β in females. In both sexes, a correlation was observed with upregulated expressions of ERK1/2 and JNK1/3 in 1% groups. On 36d, the correlation was observed with downregulated expressions of p38-MAPKα/β in males and their upregulated expressions in females. Time-dependent increase in lipid peroxidation on 15d and 36d correlated with upregulated expressions of p38-MAPKα/β in females and ERK1/2 in 1% groups in both sexes. The lower dose induced more apoptosis up to 15d in females and the higher dose induced in males on 36d. Generally, the female livers had more p38-MAPKα/β than the male livers. On 36d, the female livers showed more p38-MAPKα/β and JNK1/3 than the male livers. In conclusion, although not clearly defined, a correlation exists among oxidative stress, apoptosis, and the MAPKs in lead-exposed hepatocytes. The sex-dependent effects may be due to differences in hormonal or other physiological mechanisms. In lead-exposed hepatocytes, the apoptosis may be induced via oxidative stress-mediated alterations in the MAPKs.