Risk assessment of the lipid metabolism-disrupting effects of nitro-PAHs

Nitro-polycyclic aromatic hydrocarbons (NPAHs) are of increasing global concern due to their ubiquitous occurrence and long-range transport in the environment. However, their potential metabolism-disrupting effects, especially nuclear receptor-related lipid disorders, are still poorly understood. Targeting estrogen receptor alpha (ER alpha), this study for the first time evaluated the lipid metabolic effects of NPAHs using in vitro and in vivo models. The results indicated that four of the five NPAHs tested exhibited significant ER alpha agonistic activities, and induced increased secretion of 17 beta-estradiol (E-2) in HepG2 cells. Furthermore, lipidomic analysis showed that exposure to the candidate NPAH (3-nitrofluoranthene, 3-NFA) led to elevated hepatic levels of triacylglycerols (TAGs) and cholesteryl esters (CEs). Importantly, the lipid overload induced by 3-NFA was verified in the livers of zebrafish larvae using Oil Red O staining. Additionally, significant increases in E-2 production and the expression levels of associated genes (17 beta HSD and C/EBP-alpha) further supported the involvement of the ER alpha signaling pathway in the lipid metabolic perturbation induced by 3-NFA. These results provide novel insight into the lipid metabolism-disrupting effects induced by NPAHs and may offer a better understanding of the environmental risks of NPAHs.