miR-144-3p suppression mediates Nrf2 activation induced by developmental arsenic exposure in mice.

Developmental arsenic exposure enhances the risk for hepatic diseases in later life, which has been found to be related to Nrf2 activation. Epigenetic alterations are suggested to contribute to Nrf2 activation but the potential mechanism is to be elucidated. This study reveals that developmental exposure to 0.5 ppm arsenic induced a 1.5-fold increase in hepatic Nrf2 activity in weaned pups, as indicated by over-expression of Nrf2 and its downstream genes. Blood GSH/GSSG ratio showed a 4.4-fold increase in pups after 0.5 ppm arsenic exposure. Nrf2 deficiency attenuated arsenic-induced GSH/GSSG ratio elevation. DNA methylation at the global level and Nrf2 promoter region was not significantly altered in the liver of pups exposed to arsenic during the developmental stage. The levels of miR-144-3p and miR-27a-3p in the liver of pups were significantly decreased to 40 % and 70 % of control by 0.5 ppm arsenic exposure, respectively. The levels of miR-101a-3p and miR-155-5p in the liver of pups were significantly increased to 2.2 and 1.8-fold of control by 0.5 ppm arsenic exposure, respectively. Notably, transfection with a miR-144-3p inhibitor significantly increased mRNA levels of Nrf2 (2.2-fold) and its target genes Gsr (1.8-fold), Gclc (1.5-fold), and Gclm (2.0-fold) in primary mouse hepatocytes. Taken together, our data suggest that developmental arsenic exposure induced activation of Nrf2 via miR-144-3p suppression.