Resveratrol alleviates Mono-2-ethylhexyl phthalate-induced mitophagy, ferroptosis, and immunological dysfunction in grass carp hepatocytes by regulating the Nrf2 pathway

• Published in: Journal of environmental management 2024-12, Vol.371, p.123235, Article 123235
• Main Authors: Wang, Xiaodan, Gao, Meichen, Lu, Xiunan, Lei, Yutian, Sun, Jiatong, Ren, Mengyao, Xu, Tong, Lin, Hongjin
• Format: Article
• Language: English
• Subjects: Ferroptosis; Immune dysfunction; L8824 cells; MEHP; Mitophagy; Nrf2; Resveratrol
• ISSN: 0301-4797; 1095-8630; 1095-8630
• DOI: 10.1016/j.jenvman.2024.123235

Mono-2-ethylhexyl phthalate (MEHP) is the major biologically active metabolite of Di(2-ethylhexyl) phthalate (DEHP). This MEHP mono-ester metabolite can be transported through the bloodstream into tissues such as the liver, kidneys, fat, and testes and cause corresponding damage. Resveratrol (RSV) has anti-inflammatory, antioxidant, and detoxification characteristics. Our research examined whether RSV alleviates MEHP-induced grass carp hepatocyte (L8824 cell) injury and its relationship with the Nrf2 pathway, mitophagy, ferroptosis, and immune function. Therefore, we treated L8824 cells with 85 μM MEHP and/or 2 μM RSV. The findings indicated that exposing MEHP resulted in increased reactive oxygen species (ROS) content and decreased mitochondrial membrane potential in L8824 cells, which induced an up-regulation of the expression of mitophagy-related indicators (PINK1, Parkin, Beclin1, LC3B, and ATG5) and a down-regulation of P62. An up-regulation of the expression of the ferroptosis-related indicators TFR1 and COX-2, and GPX4 and FTH expression was down-regulated. In addition, there was a decrease in the expression of IL-2 and IFN-γ and an increase in the expression of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 after exposure to MEHP. RSV activates the Nrf2 pathway and effectively alleviates MEHP-induced mitophagy, ferroptosis, and immunologic dysfunction of L8824 cells. [Display omitted] •Exposure to MEHP can induce oxidative stress, mitophagy, ferroptosis and immune dysfunction in L8824 cells.•Resveratrol alleviate MEHP-induced mitophagy, ferroptosis and immune dysfunction by regulating the Nrf2 pathway.•Activation of Nrf2 antioxidant system can reduce the toxic effect of MEHP on L8824 cells.