Cardiotoxic Effect Induced by F-53B via Nitric Oxide Signalling on Parkin^-/- Mice

A comprehensive understanding of gene-environment interactions is essential for maintaining human cardiac health, and deficiency in the key parkin gene exacerbates cardiac injury. Per- and polyfluoroalkyl substances (PFAS) exposure has been determined cardiotoxicity from the epidemiological perspective but the potential remained unclear. Here, we investigated the co-effects on cardiac pathological structure and function of an emerging PFAS, 6:2 chlorinated polyfluorinated ether sulfonate acid (F-53B), on male parkin^-/- mice at dose of 3 and 3000 μg/kg for 60 d. Mechanism was focused on the activity, phosphorylation of endothelial nitric oxide synthase (eNOS), and the content of nitric oxide (NO), vital vascular function regulating molecule. F-53B significantly increased cardiac fibrosis to 1.58- and 2.80-fold, and cardiac troponin T (cTNT) to 1.17- and 1.32-fold compared with control group, at dose of 3 and 3000 μg/kg, respectively, indicating F-53B can inhibit the normal activities of the heart and cause functional disorders. Content and phosphorylation of eNOS significantly decreased to 0.68-, 0.67-fold, and to 0.65-, 0.54-fold compared with control group, respectively. The subsequent content of NO level was also significantly decreased to 0.47- and 0.33-fold, respectively, indicating that significant co-effects of parkin deficiency and F-53B exposure on cardiac function and structural changes via eNOS/NO signalling. Our work underscores the importance of assessing cardiac risk associated with PFAS at environmentally relevant doses, especially considering environmental exposure and gene co-interaction from the perspective of F-53B and parkin gene.