Low Levels of Perfluorooctanoic Acid Exposure Activates Steroid Hormone Biosynthesis through Repressing Histone Methylation in Rats

Abstract

Perfluorooctanoic acid (PFOA) is a persistent organic pollutant, which has endocrine-disrupting properties and can interfere with the synthesis and secretion of testicular steroid hormones, but the underlying molecular mechanisms are still not fully understood. In this study, we investigated the effects of low doses of PFOA exposure on testicular steroidogenesis in rats and revealed the role of histone modifications. It was found that the serum levels of progesterone, testosterone, and estradiol were significantly increased after 0.015 and 0.15 mg/kg of PFOA exposure, and the expression of Star, a key rate-limiting gene, was up-regulated, while other steroidogenic genes Cyp11a1, Hsd3b, Cyp17a1, and Hsd17b were down-regulated. In addition, the levels of multiple histone modifications (H3K9me1/2/3 and H3K9/18/ 23ac) were all significantly reduced by PFOA in rat testis. Histone H3K9 methylation is associated with gene silencing, while histone acetylation leads to gene activation. ChIP analysis further showed that H3K9me1/3 was significantly decreased in the promoter region of Star, while H3K18ac levels were down-regulated in other gene promoters. Accordingly, we suggest that low-level PFOA enhances StAR expression through the repression of H3K9me1/3, which stimulates steroid hormone production in rat testis. These results are expected to shed new light on the molecular mechanisms by which low-dose PFOA disturbs male reproductive endocrine from an epigenetic aspect and may be useful for human health risk assessment regarding environmental PFOA exposure.

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“…Moreover, 3 steroidogenic genes, essential for the production of sex hormones, were found to be downregulated ( cyp11c1, cyp17a1 , and star ), and one was upregulated ( ugt2a7 ) (Supporting Information – Table S5). The downregulation of star , a key rate-limiting enzyme of steroid hormones synthesis, together with cyp11c1, cyp17a1 , could indicate a disruption of the homeostatic regulation of steroids . These findings are also in agreement with the significant decrease in cholesterol levels in the livers of MET exposed males reported in our parallel study, as cholesterol is the sole precursor of steroid hormones, , and are also associated with the upstream deregulation of genes coding energy/lipid metabolism processes.…”

“…The downregulation of star, a key rate-limiting enzyme of steroid hormones synthesis, together with cyp11c1, cyp17a1, could indicate a disruption of the homeostatic regulation of steroids. 66 These findings are also in agreement with the significant decrease in cholesterol levels in the livers of MET exposed males reported in our parallel study, 3 as cholesterol is the sole precursor of steroid hormones, 67,68 and are also associated with the upstream deregulation of genes coding energy/lipid metabolism processes. Finally, we noted 49 downregulated genes linked to reproductive processes, most of them involved in gametogenesis/sex differentiation (e.g., amh, ddx4, dmrt1, piwil1, and spata4) and sperm motility (e.g., dnaah1, dnai1.1, dnaaf 2, and spef1) (Supporting Information − Table S5).…”

Rebuttal to Correspondence on “Low Levels of Perfluorooctanoic Acid Exposure Activates Steroid Hormone Biosynthesis through Repressing Histone Methylation in Rats”

“…Furthermore, the serum PFOA concentration ranged from 3.53 to 7.86 μg/mL in rats after PFOA exposure for 2 months, a range that is comparable to the serum concentration range in humans occupationally exposed to PFOA (0.11–6.8 μg/mL) . This is due to the accumulation of PFOA in rat serum after exposure for 2 months, indicating the bioaccumulation of PFOA …”

“…In our Article, for the statement “the average serum concentrations of PFOA in the general populations are 1.4–88.1 μg/L, which approximately corresponds to 1.4–88.1 μg/kg bw”, it was just a unit conversion from micrograms per liter to micrograms per kilogram based on the average human body density (∼1 kg/L), not the metric conversion from serum volume (liters) to body weight (kilograms).…”

Correspondence on “Low Levels of Perfluorooctanoic Acid Exposure Activates Steroid Hormone Biosynthesis through Repressing Histone Methylation in Rats”

“…Han et al conducted animal experiments to evaluate the effect of “low-level” perfluorooctanoic acid (PFOA) exposure on steroid hormone biosynthesis . However, we have concerns about the dose selection.…”