Abstract
Perfluorooctanoic acid (PFOA) is an abundant perfluoroalkyl substance widely applied in industrial and consumer products. It is a ubiquitous environmental pollutant and suspected endocrine disruptor. Corticosteroid-binding globulin (CBG) is a monomeric glycoprotein that can bind specifically to anti-inflammatory steroids, such as glucocorticoids and progesterone, in circulation. Our previous proteomic profile analysis revealed that CBG levels increased in testes after PFOA treatment. In the present study, we verified its increase in mouse testes following oral exposure to PFOA (0, 1.25 and 5 mg/kg/day for 28 days) by immunohistochemical analysis and Western blotting. In addition, RNA fluorescence in situ hybridization (FISH) confirmed that testicular CBG was specifically expressed in Leydig cells. Serum CBG levels in all three PFOA groups also increased, accompanied by increased corticosterone in the 5 and 20 mg/kg/day groups and decreased adrenocorticotropic hormone in the 20 mg/kg/day group. Thus, the influence of PFOA on blood CBG may change free steroid hormone concentrations, thereby serving as an endocrine disruptor. A stimulation effect of PFOA on CBG was also observed in vitro using the Leydig tumor mLTC-1 cell line. Overexpression of CBG in mLTC-1 cells increased progesterone release in culture media. In addition, CBG-induced proteins involved in steroidogenesis in mLTC-1 cells, including steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (CYP11A1), 17α-hydroxylase/17,20 lyase (CYP17A1), and 3β-hydroxysteroid dehydrogenase (3β-HSD), which may be the mechanism behind increased progesterone. Furthermore, the production and release of CBG in mLTC-1 cells were also induced by luteinizing hormone, though this mechanism requires further exploration.
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Abbreviations
- CYP17A1:
-
17α-Hydroxylase/17,20 lyase
- 3β-HSD:
-
3β-Hydroxysteroid dehydrogenase
- ACTH:
-
Adrenocorticotropic hormone
- CBG:
-
Corticosteroid-binding globulin
- CRH:
-
Corticotrophin-releasing hormone
- CYP11A1:
-
Cytochrome P450 cholesterol side-chain cleavage enzyme
- HPA:
-
Hypothalamic–pituitary–adrenal
- LH:
-
Luteinizing hormone
- ORF:
-
Open reading frame
- PFASs:
-
Perfluoroalkyl substances
- PFOA:
-
Perfluorooctanoate
- RCL:
-
Reactive center loop
- StAR:
-
Steroidogenic acute regulatory protein
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (31320103915, 21737004, and 21377128). We thank Prof. Geoffrey L. Hammond from the Departments of Cellular and Physiological Sciences and Obstetrics and Gynaecology, University of British Columbia, Canada, for providing CBG antibodies.
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Sun, S., Wang, J., Lu, Y. et al. Corticosteroid-binding globulin, induced in testicular Leydig cells by perfluorooctanoic acid, promotes steroid hormone synthesis. Arch Toxicol 92, 2013–2025 (2018). https://doi.org/10.1007/s00204-018-2207-y
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DOI: https://doi.org/10.1007/s00204-018-2207-y