Bisphenol A exposure induces testicular oxidative damage via FTO/m6A/Nrf2 axis during postnatal development in mice. Issue 5 (19th February 2023)

• Record Type: Journal Article
• Authors: Ling, Yuanchao; Huang, Xiaodi; Li, Anlong; Zhang, Jinzhi; Chen, Jianmei; Ren, Jiale; Liu, Yanan; Xie, Meina
• Is Part Of: Journal of applied toxicology. Volume 43:Issue 5(2023)
• Page Start: 694
• Page End: 705
• Publication Date: 2023-02-19
• Subjects: Bisphenol A -- FTO -- m6A modification -- Nrf2 -- testis; Toxicology -- Periodicals; Industrial toxicology -- Periodicals; Environmentally induced diseases -- Periodicals; Toxicology -- Periodicals; 615.9005
• DOI: 10.1002/jat.4417
• Languages: English
• ISSNs: 0260-437X

Abstract

Abstract: Bisphenol A (BPA), a commonly used plasticizer in the production of polycarbonate plastics and epoxy resins, has been shown to induce male reproductive toxicity. However, the effects of BPA exposure on early testicular development have not been thoroughly studied, and the underlying mechanism is yet to be elucidated. In the current study, neonatal male mice were exposed to BPA at 0, 0.1, and 5 mg/kg, respectively, by daily subcutaneous injection during postnatal day (PND) 1–35 to explore its effects on testicular development at PND 36 (the end of the first round of spermatogenesis). Morphological analyses showed that BPA exposure significantly induced apoptosis of testicular cells ( p < 0.01 and p < 0.001) and reduced the thickness of seminiferous epithelium ( p < 0.01). In addition, BPA exposure significantly decreased the total antioxidant capacity of testes and levels of transcription factor Nrf2 as well as its downstream antioxidant molecules of NQO1 and GPx‐1 ( p < 0.05 and p < 0.01). Furthermore, global m6A modifications of mRNAs were upregulated accompanied by declined m6A demethylase (FTO) in the testes of BPA groups ( p < 0.05 and p < 0.01). MeRIP‐quantitative real‐time polymerase chain reaction (qPCR) demonstrated that BPA exposure markedly increased the m6A modification of Nrf2 mRNA ( p < 0.05 and p < 0.01). These findings suggest that upregulation of m6A induced by inhibited FTO may be involved in BPA‐induced testicular oxidative stress and developmental injury during postnatal development, which provides a new idea to reveal the mechanism underlying BPA interfering with testicular development. Abstract : Neonatal mice were exposed to BPA during the first round of spermatogenesis to explore its effects on testicular development. We found that BPA exposure induced testicular oxidative damage by downregulating testicular expression of Nrf2 and its downstream antioxidant molecules. Furthermore, BPA inhibited testicular FTO expression and elevated the total m6A RNA modifications in testes. The downregulation of Nrf2 protein induced by BPA may result from the elevated m6A modifications of Nrf2 mRNA.