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BPA induces placental trophoblast proliferation inhibition and fetal growth restriction by inhibiting the expression of SRB1

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Abstract

Bisphenol-A (BPA) is a common environmental toxicant that is known to be associated with fetal growth restriction (FGR). However, the mechanisms of how BPA induce FGR is poorly characterized. We conducted proteomics to identify the abnormal expression of SRB1 in female placental tissues with high BPA-induced FGR and further verified its decreased expression in human placenta and BeWo cells. Next, the effect of BPA on fetal development was further confirmed in pregnant C57BL/6 mice. The expression of SRB1 was consistently downregulated in human FGR placentas, BPA-exposed trophoblasts and mouse placentas. In addition, we found that SRB1 interacted with PCNA, and BPA exposure indirectly reduced the expression of PCNA and further inhibited placental proliferation. In vitro studies showed that BPA exposure reduced the expression of CDK1, CDK2, cyclin B and phosphorylated Rb in placental trophoblast cells, indicating cell cycle arrest after exposure to BPA. In addition, the expression of γ-H2AX and phosphorylated ATM was upregulated in BPA-exposed trophoblasts, indicating increased DNA damage. Our results indicate that BPA-induced FGR is achieved by reducing the expression of SRB1, inhibiting placental proliferation and increasing DNA damage. Our findings not only explain the mechanism of BPA-associated developmental toxicity but also shed light upon developing novel therapeutic targets.

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Acknowledgements

This work is supported by research grant (No.81771543) from the National Natural Science Foundation of China.

Funding

This work is supported by the China National Natural Science Foundation grant (No.81771543).

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Authors and Affiliations

  1. Department of Gynaecology and Obstetrics, Zhongnan Hospital of Wuhan University, No 169 of Donghu Road, Wuhan, 430071, Hubei, China

    Yuming Cao, Jing Lu, Ming Zhang & Yuanzhen Zhang

  2. Reproductive Medicine Center, Zhongnan Hospital of Wuhan University, Wuhan, China

    Yuming Cao, Ming Zhang, Lei Shi, Juling Qin, Jing Lv, Danyang Li, Ling Ma & Yuanzhen Zhang

  3. Department of Gynaecology and Obstetrics, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, People’s Republic of China

    Yuming Cao & Yuanzhen Zhang

  4. School of Basic Medical Sciences, Wuhan University, Wuhan, China

    Sihan Chen

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  1. Yuming Cao
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  2. Sihan Chen
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  3. Jing Lu
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  4. Ming Zhang
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  5. Lei Shi
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  6. Juling Qin
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  10. Yuanzhen Zhang
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Contributions

Most of the experiments and data analysis as well as manuscript preparation were conducted by Yuming Cao. Danyang Li made the patients informed consent and asked them to sign the informed consent form. Jing Lu, Ming Zhang and Lei Shi collects clinical samples and patient information. Immunoprecipitation was conducted by Juling Qin and Jing Lv. The Bioinformatics analysis was performed by Ling Ma. Study design and the final revision of the manuscript was accomplished by Yuanzhen Zhang.

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Correspondence to Yuanzhen Zhang.

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The study was approved by the Ethics Committee of Zhongnan Hospital of Wuhan University (No. 2018047).

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Cao, Y., Chen, S., Lu, J. et al. BPA induces placental trophoblast proliferation inhibition and fetal growth restriction by inhibiting the expression of SRB1. Environ Sci Pollut Res 30, 60805–60819 (2023). https://doi.org/10.1007/s11356-023-26850-4

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