Key Laboratory of Environment and Female Reproductive Health, West China School of Public Health & West China Fourth Hospital, Sichuan University, Chengdu, 610041, China; Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China.
Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China.
Environ Pollut. 2024 May 1;348:123847. doi: 10.1016/j.envpol.2024.123847. Epub 2024 Mar 27.
Copper pollution has become global environmental concern. Widespread Cu pollution results in excessive Cu exposure in human. Epidemiological studies and animal experiments revealed that Cu exposure might have reproductive toxicity. Cuproptosis is a newly reported Cu-dependent and programmed cell death formTsvetkov et al., 2022. However, whether copper exposure at real environmental exposure dose might cause placental cuproptosis and induce miscarriage was completely unexplored. In this study, we found that Cu exposure during pregnancy induced miscarriage or complete pregnancy loss by inducing placenta cuproptosis in CuCl-exposed pregnant mice. Notably, Cu exposure at 1.3 mg/kg/d (a real environmental exposure dose) was enough to cause placenta cuproptosis. CuCl exposure disrupts the TCA cycle, causes proteotoxic stress, increases Cu ion import/decreases Cu export, and results in the loss of Fe-S cluster proteins in mouse placenta, which induces placenta cuproptosis. Moreover, we also identified that Cu exposure down-regulates the expression levels of mmu-miR-3473b, which interacts with Dlst or Rtel1 mRNA and simultaneously positively regulates Dlst or Rtel1 expression, thereby disrupting the TCA cycle and resulting in the loss of Fe-S cluster proteins, and thus epigenetically regulates placental cuproptosis. Treatment with TTM (a cuproptosis inhibitor) suppressed placental cuproptosis and alleviated miscarriage in CuCl-exposed mice. This work provides novel reproductive toxicity of Cu exposure in miscarriage or complete pregnancy loss by causing placental cuproptosis. This study also provides new ways for further studies on other toxicological effects of Cu and proposes a new approach for protection against Cu-induced reproductive diseases.
铜污染已成为全球性的环境问题。广泛的铜污染导致人类暴露于过量的铜。流行病学研究和动物实验表明，铜暴露可能具有生殖毒性。铜死亡是一种新报道的铜依赖性和程序性细胞死亡形式，Tsvetkov 等人，2022 年。然而，在真实环境暴露剂量下，铜暴露是否会导致胎盘铜死亡并引起流产，这仍然完全未知。在这项研究中，我们发现，在怀孕的小鼠中暴露于铜会通过诱导胎盘铜死亡而导致流产或完全妊娠丢失。值得注意的是，暴露于 1.3mg/kg/d 的铜（真实的环境暴露剂量）足以引起胎盘铜死亡。铜暴露破坏三羧酸循环，导致蛋白毒性应激，增加铜离子内流/减少铜输出，并导致小鼠胎盘中铁硫簇蛋白的丢失，从而诱导胎盘铜死亡。此外，我们还发现，铜暴露下调 mmu-miR-3473b 的表达水平，该 miR-3473b 与 Dlst 或 Rtel1 mRNA 相互作用，并同时正向调节 Dlst 或 Rtel1 的表达，从而破坏三羧酸循环并导致铁硫簇蛋白丢失，从而在表观遗传水平上调节胎盘铜死亡。用 TTM（一种铜死亡抑制剂）治疗可抑制胎盘铜死亡并缓解 CuCl 暴露小鼠的流产。这项工作为铜暴露通过引起胎盘铜死亡导致流产或完全妊娠丢失提供了新的生殖毒性证据。该研究还为进一步研究铜的其他毒性作用提供了新的途径，并提出了一种预防铜引起的生殖疾病的新方法。
