Comparative steroidogenic effects of hexafluoropropylene oxide trimer acid (HFPO-TA) and perfluorooctanoic acid (PFOA): Regulation of histone modifications

As a widely used alternative to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPOTA) has been detected in the environment and humans; however, little is known regarding its male reproductive toxicity. To compare the effects of HFPO-TA on steroid hormone synthesis with PFOA, we exposed Leydig cells (MLTC-1) to non-lethal doses (0.1, 1, and 10 mu M) of PFOA and HFPO-TA for 48 h. It was found that the levels of steroid hormones, 17a-hydroxyprogesterone (OHP), androstenedione (ASD), and testosterone (T) were significantly increased in 1 and 10 mu M of PFOA and HFPO-TA groups, with greater elevation being observed in the HFPO-TA groups than in the PFOA groups at 10 mu M. We further showed that the two rate-limiting steroidogenic genes (Star and Cyp11a1) were up-regulated, while Hsd3b, Cyp17a1, and Hsd17b were down-regulated or unchanged after PFOA/HFPO-TA exposure. Moreover, PFOA exposure significantly up-regulated histone H3K4me1/3 and H3K9me1, while down-regulated H3K4me2 and H3K9me2/3 levels. By contrast, H3K4me2/3 and H3K9me2/3 were enhanced, while H3K4me1 and H3K9me1 were repressed after HFPO-TA treatment. It was further confirmed that H3K4me1/3 were increased and H3K9me2 was decreased in Star and Cyp11a1 promoters by PFOA, while HFPO-TA increased H3K4me2/3 and decreased H3K9me1 in the two gene promoters. Therefore, we propose that low levels of PFOA/HFPO-TA enhance the expression of Star and Cyp11a1 by regulating H3K4 and H3K9 methylation, thus stimulating the production of steroid hormones in MLTC-1 cells. Collectively, HFPOTA exhibits stronger effects on steroidogenesis compared to PFOA, which may be ascribed to the distinct regulation of histone modifications. These data suggest that HFPO-TA does not appear to be a safer alternative to PFOA on the aspect of male reproductive toxicity.