Chronic Exposure to Lead Causes Neurotoxicity by Generating Oxidative Stress and Inducing DNA Damages in Zebrafish Brain: Involvement of Nrf2-Keap1 Regulation and DNA Repair Pathways

Toxicity of lead (Pb) causes several health problems in human beings. The present study reveals the potential effects of Pb on adult zebrafish (Danio rerio) brain at an environmentally relevant concentration. Pb generated reactive oxygen species-mediated oxidative stress, as evidenced by alterations of GSH, MDA levels, and CAT activity. The Nrf2-Keap1 pathway counteracted this stress as a part of cytoprotection. The gene expression and immunolocalization studies confirmed the augmentation of Nrf2 in the brain. Activation of the Nrf2-Keap1 pathway influenced downstream nqo1 and ho1 gene expressions. The alterations in histopathology and mRNA expressions of biomarker genes like hsp70 and ache revealed the toxic insults of Pb in the brain. DNA damage assay verified the genotoxic potential of Pb. The expression pattern of the candidate genes of two critical repair pathways (base excision and mismatch repair) was studied to assess the DNA damage responses. The damages in DNA caused by 15 days of Pb exposure were sufficient to trigger the expression of BER (ogg1, apex1, pol beta, and creb1) and MMR (msh2, msh6, and mlh1) genes to protect cells. Chronic exposure for 30 days suppressed both the machinery, predisposing mutations. The overexpression of crucial tumor suppressor genes p53 and brca2 indicated their protective role against cancer progression. Understanding the molecular mechanisms underlying Pb-induced neurotoxicity and the DNA damage response may help to improve our current knowledge for the prevention of Pb poisoning.