Di(2-ethylhexyl) phthalate induced hepatotoxicity in quail (Coturnix japonica) via modulating the mitochondrial unfolded protein response and NRF2 mediated antioxidant defense

Among ubiquitously found environmental contaminants in the ecosystem, di(2-ethylhexyl) phthalate (DEHP) is an important environmental contaminant used as plasticizer in medical and consumer goods. The bioaccumulation and environmental persistence of DEHP cause serious global health effects in wildlife animals and human, especially hepatotoxicity. Herein, to explore the mechanisms of DEHP induced hepatotoxicity, quail were exposed with 0, 250, 500 and 1000 mg/kg BW/day DEHP by gavage administration daily for 45 days. Notably, the adipose tissue degeneration was observed in the liver of DEHP-exposed quail under the histopathological analysis. DEHP exposure increased the peroxidation product (MDA), GSH and GST, but decreased antioxidant function (T-AOC, SOD and GPX). DEHP induced the oxidative stress and pulsed on NRF2 signal pathway through activating downstream genes. Furthermore, DEHP induced mitochondrial ultrastructural abnormalities and mitochondrial dysfunctions. Mitochondrial unfolded protein response (mtUPR) was activated to relieve mitochondrial dysfunctions and mitigated oxidative stress. These findings showed that mitochondrial functions and redox homeostasis were affected by DEHP and resulted in irreversible hepatic injury. In Conclusion, this study suggested that DEHP-induced hepatotoxicity in quail was associated with activating the NRF2 mediated antioxidant defense and mtUPR. These results provided new evidence on molecular mechanism of DEHP induced hepatotoxicity. • DEHP causes hepatotoxicity through oxidative stress. • DEHP causes mitochondrial ultrastructural abnormality and dysfunctions. • DEHP triggers the Nrf2-mediated antioxidant defense. • MtUPR relieves DEHP-induced mitochondrial damage.