4.6 Article

In utero bisphenol AF exposure causes fetal Leydig cell dysfunction and induces multinucleated gonocytes by generating oxidative stress and reducing the SIRT1/PGC1α signals

Journal

TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 447, Issue -, Pages -

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2022.116069

Keywords

Fetal Leydig Cell; Bisphenol AF; Testosterone; Reactive Oxygen Species; SIRT1

Funding

  1. NSFC of China [81730042]

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BPAF exposure in pregnant rats was found to have adverse effects on fetal Leydig cells and germ cells, leading to male reproductive tract malformation. These effects were mediated by interference with steroidogenic networks, suppression of the antioxidant defense system, reduction of SIRT1 and PGC1 alpha signals, and increased AMPK phosphorylation.
Bisphenol AF (BPAF) is one of the primary alternatives of bisphenol A. It has been ubiquitously detected in the environment and is an emerging endocrine disrupting compound. However, the effects of BPAF exposure on fetal Leydig cells and germ cells and the underlying mechanisms remain largely unknown. To this end, pregnant Sprague-Dawley rats were exposed to 10, 50, and 200 mg/kg/d BPAF by gavage from gestational days 14 to 21. The neonatal rats were sacrificed on day 1 at birth. The results showed that serum testosterone levels were significantly decreased at 50 and 200 mg/kg/d, the expression of Scarb1, Star, Cyp17a1, Hsd17b3, and Dhh and their proteins were markedly down-regulated at 50 and 100 mg/kg/d. BPAF exposure also significantly increased the incidence of multinucleated gonocytes at 200 mg/kg/d. We further detected significant increase of testicular malondialdehyde levels and reduction of antioxidants, including SOD1, SOD2, and CAT at 50 and/or 200 mg/kg/ d. Furthermore, BPAF markedly reduced the levels of SIRT1 and PGC1 alpha at 200 mg/kg/d while significantly increased AMPK phosphorylation in the testes at 50 and 200 mg/kg/d. In conclusion, our results provide novel in vivo data that BPAF can induce fetal Leydig cell dysfunction by interfering with steroidogenic networks and induce the formation of multinucleated gonocytes after suppressing the antioxidant defense system and reducing SIRT1 and PGC1 alpha signals and increasing the phosphorylation of AMPK, which highlights the potential health risk of environmental exposure to BPAF in inducing male reproductive tract malformation.

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