Di (2-ethylhexyl) phthalate induces cholestasis liver injury in mice associated with promoting macrophage polarization through NRF2 signaling pathway

Diethylhexyl phthalate (DEHP) as a common environmental pollutant has toxic effects on a variety of biological systems, including liver toxicity and immunotoxicity. Previously we had demonstrated that DEHP cause cholestatic liver injury, but whether macrophages play a role in this is unclear, and few studies have focused on the direct effects of DEHP on macrophages. Therefore, this study investigated whether DEHP affects macrophages in vivo and the mechanism by which DEHP regulates macrophages in vitro. The results showed that DEHP induced cholestatic liver injury by up-regulating TBA levels of serum and liver. Simultaneously, DEHP increased the number of F4/80 positive macrophages and promoted the transcriptional level of IL-1β and IL-6 in liver tissue. Further in vitro, We found that DEHP decreased M2 macrophage marker Arg1 level and increased the levels of M1 macrophage marker iNOS, accompanied by up-regulation of the transcriptional levels of IL-1β, TNF-α and CCl₂. Moreover, DEHP increased glycolytic flux, which was confirmed by the increased Glut1, HK2 and pfkfb3 expression. Mechanistically, we found DEHP inhibited NRF2 activation, and down-regulated the expression of downstream target NOQ1. While, CDDO (an NRF2 activator) could abrogate the promotion of DEHP on M1 macrophage polarization and glycolysis. These findings indicated that promotion effect of DEHP on M1 macrophage polarization is associated with regulating energy metabolism of macrophages through NRF2/NQO1 pathway.