Zinc attenuates arsenic overdose-induced brain damage via PERK/ATF6 and TLR/MyD88/NF-κB pathways

Abstract

Exposure to arsenic (As), a widespread non-metallic toxicant in nature, often results in neurotoxicity, although the exact mechanism is unknown. Zinc (Zn) is a powerful nutrient often thought to be beneficial for growth, development and immunity. Whether Zn can rescue brain damage caused by As contamination remains to be demonstrated. Therefore, in this study, a 30-day model of As poisoning (2.83 mg/L) in carp was established and treated with Zn (1 mg/L) to investigate the detoxification mechanism involved. Histological observations showed that As induced the loosening of the molecular layer structure of the cerebellum and the dissolution or even disappearance of nuclei, accompanied by the occurrence of microthrombi in the granular layer, and the addition of Zn attenuated such As-induced damage. Further mechanistic studies indicated that Zn ameliorated As exposure-induced abnormalities in antioxidant capacity (decreased CAT and Cu/Zn-SOD), activation of the Nrf2/keap1 pathway and endoplasmic reticulum stress (ERs), which is a key factor in As-induced brain damage. ERs (high expression of PERK, ATF6, CHOP, eiF2α and GRP78) and inflammation (overexpression of TLR2, TLR4, MyD88, IKK, NF-κB, IL-1β and IL-6 and low expression of IκBα and IL-10). We suggest that Zn can alleviate excessive As-induced brain damage by attenuating As-induced oxidative stress, PERK/ATF6 and TLR/MyD88/NF-κB pathways. The present study fills in the preventive mechanism of As injury in fish and provides the possibility of prevention and control of As pollution-induced brain tissue injury by Zn rescue.