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

TL;DR

This study shows that a chemical called VCD causes mouse ovarian failure by reducing a key protein and triggering too much cell cleanup, leading to loss of egg cells.

Contribution

The study reveals a novel mechanism linking VCD exposure to ovarian failure through IGF1R downregulation and excessive autophagy.

Findings

VCD downregulates IGF1R in ovarian granulosa cells, inhibiting the IGF1R/AKT/mTOR signaling pathway.

VCD-induced IGF1R inhibition triggers excessive autophagy flux in human granulosa-like tumor cells.

Excessive autophagy caused by VCD leads to premature follicle activation and loss of ovarian function.

Abstract

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.

The online version contains supplementary material available at 10.1007/s44154-024-00197-3.

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