Heme-oxygenase-1 as a target for phthalate-induced cardiomyocytes ferroptosis

Abstract

Phthalates as a large group of environmental pollutants are used primarily as plasticizers and solvents, which have become a growing problem worldwide. Epidemiological results show that severity of heart disease is related to degree of environmental contamination. As the most usually used phthalate, di(2-ethylhexyl) phthalate (DEHP) has toxic effects on organism health and is also a major cause of heart damage. Ingestion of food, liquid, or dust contaminated with DEHP are major routes of exposure. The purpose of the present research was to determine the mechanism of cardiotoxicity in mice after exposure to DEHP. Here, male mice were treated by gavage with three different doses of (50, 200 and 500 mg/kg b.w.) DEHP for 28 days. Our research showed that DEHP brought about histopathological changes involving cardiomyocyte lysis and rupture, and ultrastructural damage such as dissolution and loss of mitochondrial cristae. Furthermore, DEHP induced oxidative stress and a significant decline in the antioxidant function, which activates nuclear factor E2-related factor 2 (Nrf2)/heme-oxygense-1 (HO-1) signaling pathways. Interestingly, DEHP resulted in lipid peroxidation and increased ferrous ion content, suggesting that ferroptosis occurred in mouse hearts. Therefore, our findings demonstrated that DEHP could induce cardiac ferroptosis via upregulation of HO-1. The present study provides novel evidence of HO-1 as a target for DEHP-induced cardiotoxicity.