Effects of perfluoroalkyl substances on neurosteroid synthetic enzymes in the rat

Xu, Ren-ai; Shen, Qiuxia; Li, Senlin; Li, Xiaojun; Li, Huitao; Lü, Yao; Lian, Qingquan; Ge, Ren‐Shan

doi:10.1016/j.cbi.2017.05.017

Cited by 9 publications

(3 citation statements)

References 18 publications

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“…Nevertheless, the similar compensatory mechanism has appeared in perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) exposures. PFOS and PFOA competitively depressed rat SRD5A1 activity, thereby controlling the biosynthesis of neurosteroids [26].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 96%

Triclosan Suppresses Testicular Steroidogenesis via the miR-6321/JNK/ Nur77 Cascade

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Triclosan (TCS), a broad-spectrum antibacterial and antifungal compound and an endocrine disruptor, has anti-androgenic properties and could adversely affect male reproduction and fertility. Methods: To elucidate the underlying roles of miRNAs and the MAPK pathway in TCS-mediated repression of testicular steroidogenesis, Sprague-Dawley male rats were dosed daily with TCS for 31 days, and TM3 cells were exposed to TCS for 24 h after the pretreatments with the activator of JNK, Nur77 siRNA, or recombinant lentivirus vector for Nur77. Tissues and/or cells were analyzed by several techniques including transmission electron microscopy, lentivirus production, overexpression, gene silencing, luciferase reporter assay, chromatin immunoprecipitation, western blot, and real-time PCR. Results: TCS caused histopathologic alterations in the testis and reduced plasma LH and testicular testosterone. TCS induced miR-6321 expression, which in turn depressed its target gene, Map3k1. The inhibition of Map3k1 subsequently inactivated its downstream JNK/c-Jun pathway. ChIP and qPCR assays confirmed that c-Jun directly bound to the Nur77 DNA promoter regions to regulate Nur77 expression. The knockdown and overexpression of Nur77 demonstrated that the JNK/c-Jun-mediated decline in the transcription and translation of Nur77 resulted in the depression of steroidogenic proteins including SRB1, StAR, and 3β-HSD. Intriguingly, the protein expressions of 5α-Reductases (SRD5A1 and SRD5A2) were also downregulated after TCS exposure. Conclusion: Taken together, the miR-6321/Map3k1-regulated JNK/c-Jun/ Nur77 cascade contributes to TCS-caused suppression of testicular steroidogenesis, and the decrease in 5α-Reductase expressions may be the compensatory mechanism.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 96%

Triclosan Suppresses Testicular Steroidogenesis via the miR-6321/JNK/ Nur77 Cascade

Zhang

et al. 2018

Cell Physiol Biochem

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“…For our concern, PFOA has also been shown to be associated with reproductive toxicity. For example, PFOA may cause infertility in males, as it affects both LC function and spermatogenesis 25–27 . Nine perfluoroalkyl acids (PFAAs), including PFOA, have been demonstrated to be negatively correlated with sperm mobility 28 .…”

Section: Introductionmentioning

confidence: 99%

“…For example, PFOA may cause infertility in males, as it affects both LC function and spermatogenesis. [25][26][27] Nine perfluoroalkyl acids (PFAAs), including PFOA, have been demonstrated to be negatively correlated with sperm mobility. 28 This is supported by an in vitro study showing that PFOA may affect human spermatogenesis by targeting spermatogonial stem cells.…”

mentioning

confidence: 99%

Perfluorooctanoic acid inhibits androgen biosynthesis in rat immature Leydig cells

Zhang,

Hu,

2023

Environmental Toxicology

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Perfluorooctanoic acid (PFOA) is a commonly used short‐chain synthetic perfluoroalkyl agent. Immature Leydig cells (ILCs) are localized in the testis and responsible for androgen biosynthesis and metabolism. Although PFOA shows toxicity in the reproductive system, it is not clear if it disrupts the function of ILCs. In the present study, primary ILCs were isolated from 35‐day‐old rats and exposed to a range of PFOA concentrations (0, 0.01, 0.1, or 1 μM). It was determined that 0.1 or 1 μM PFOA reduced total androgen biosynthesis in ILCs. Specifically, 22R‐hydroxycholesterol (22R), and pregnenolone (P5) mediated androgen biosynthesis were reduced by 0.1 μM PFOA. PFOA also selectively downregulated mRNA and protein expressions of steroidogenic enzymes including LHCGR, CYP11A1, 3β‐HSD1, and NR5A1 at 0.01, 0.1, or 1 μM. Further analysis revealed that 0.1 μM PFOA inhibited CYP11A1 and 3β‐HSD1 enzyme activities. However, PFOA did not significantly affect androgen metabolism and turnover under any of the conditions tested. And PFOA gavaging to 35‐day‐old rats at 5 or 10 mg/kg for 7 or 14 days also reduced serum androgen levels secreted by ILCs. Moreover, PFOA gavaging also downregulated the mRNA and protein expression levels of LHCGR, CYP11A1, 3β‐HSD1, and NR5A1 in vivo. Taken together, these findings suggest that PFOA inhibits androgen biosynthesis in ILCs by selectively targeting key enzymes in the synthesis pathway.

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Perfluoroalkyl substances cause Leydig cell dysfunction as endocrine disruptors

Zhu

Zhu³

et al. 2020

Chemosphere

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Effects of perfluoroalkyl substances on neurosteroid synthetic enzymes in the rat

Cited by 9 publications

References 18 publications

Triclosan Suppresses Testicular Steroidogenesis via the miR-6321/JNK/ Nur77 Cascade

Triclosan Suppresses Testicular Steroidogenesis via the miR-6321/JNK/ Nur77 Cascade

Perfluorooctanoic acid inhibits androgen biosynthesis in rat immature Leydig cells

Perfluoroalkyl substances cause Leydig cell dysfunction as endocrine disruptors

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