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<p>The 4-Vinylcyclohexene dioxide (VCD) is a common occupational chemical which can lead to ovary toxicity. Autophagy is an evolutionarily conserved process that is crucial for regulating the follicular development during the whole reproductive lifespan. In order to study the effect and mechanism of VCD on autophagy in ovary, VCD was intraperitoneally injected into mouse to induce ovary toxicity model. The results showed that VCD inhibited IGF1R/AKT/mTOR signaling pathway by down-regulating the expression of IGF1R in ovarian granulosa cells (GCs) and induced autophagy in ovaries. In in vitro experiments further demonstrated that by VCD-induced IGF1R inhibition or siRNA-mediated IGF1R knockdown could trigger excessive autophagy flux in human granulosa-like tumor cell line KGN cells. Moreover, SC79, the activator of the IGF1R/AKT/mTOR signaling pathway could inhibit the excessive autophagy led by siRNA-mediated IGF1R knockdown or VCD treatment in KGN cells. Functionally, as a result of VCD-triggered excessive autophagy, VCD induced WT1 selective degradation by autophagy leading to premature differentiation of ovarian GCs and the premature activation of primordial follicles. In conclusion, VCD inhibits IGF1R/AKT/mTOR signaling pathway by downregulating the expression of IGF1R and triggers excessive autophagy in ovarian GCs, leading to abnormal GCs function and the consumption of ovarian follicle pool.</p>

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The 4-vinylcyclohexene dioxide induced mouse ovarian premature failure is caused by down regulation of IGF1R and triggering excessive autophagy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月21日

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  • Yuwei Niu,
  • Yuyang Miao,
  • Wenjing Wan,
  • Qiankun Wang,
  • Yingwan Ma,
  • Menghao Pan,
  • Baohua Ma,
  • Qiang Wei

摘要

The 4-Vinylcyclohexene dioxide (VCD) is a common occupational chemical which can lead to ovary toxicity. Autophagy is an evolutionarily conserved process that is crucial for regulating the follicular development during the whole reproductive lifespan. In order to study the effect and mechanism of VCD on autophagy in ovary, VCD was intraperitoneally injected into mouse to induce ovary toxicity model. The results showed that VCD inhibited IGF1R/AKT/mTOR signaling pathway by down-regulating the expression of IGF1R in ovarian granulosa cells (GCs) and induced autophagy in ovaries. In in vitro experiments further demonstrated that by VCD-induced IGF1R inhibition or siRNA-mediated IGF1R knockdown could trigger excessive autophagy flux in human granulosa-like tumor cell line KGN cells. Moreover, SC79, the activator of the IGF1R/AKT/mTOR signaling pathway could inhibit the excessive autophagy led by siRNA-mediated IGF1R knockdown or VCD treatment in KGN cells. Functionally, as a result of VCD-triggered excessive autophagy, VCD induced WT1 selective degradation by autophagy leading to premature differentiation of ovarian GCs and the premature activation of primordial follicles. In conclusion, VCD inhibits IGF1R/AKT/mTOR signaling pathway by downregulating the expression of IGF1R and triggers excessive autophagy in ovarian GCs, leading to abnormal GCs function and the consumption of ovarian follicle pool.