Mixture of arsenic and chromium alters antioxidant, DNA repair and tumor suppressor gene expressions in zebrafish brain at environmental concentrations

Abstract

Arsenic (As) and chromium (Cr) are two harmful toxicants as well as carcinogens which can coexist in polluted surface water and groundwater. This coexistence leads to mixture effects in animals including fish. Both of these heavy metals are reported to manifest reactive oxygen species (ROS) mediated toxicity. Though individual neurotoxic effects have been reported, their mixture effects, its mechanism and cellular responses against oxidative stress and DNA damages remain unknown. The present study evaluated the individual and mixture effects of As and Cr at their environmentally relevant concentrations in zebrafish (Danio rerio) brain after 15, 30 and 60 days of exposure. Nrf2, a transcription factor is involved in the expressional regulation of enzymes needed to maintain cellular redox homeostasis. This study reported the expressional pattern of Nrf2 and its associated xenobiotic metabolizing enzyme Nqo1 and other markers of oxidative stress such as ROS generation, reduced glutathione level, lipid peroxidation and catalase activity. Increased malondialdehyde (MDA) content, glutathione level, and catalase activity indicated oxidative stress in exposed groups. In addition, this study revealed expressional alterations of neurotoxicity marker (ache), DNA repair (ogg1, apex1, creb1, polb, mlh1, msh2 and msh6) and tumor suppressor (p53, brca2) genes. Results of ROS generation, MDA level, histopathological analysis, gene expression and immunofluorescence study confirmed that As and Cr did not show antagonistic effects in combination rather indicated additive effects which was dose-dependent but not always linear.