The occupational chemical 4-Vinylcyclohexene diepoxide (VCD) is a reproductively toxic environmental pollutant that causes follicular failure, leading to premature ovarian insufficiency (POI), which significantly impacts a woman\'s physical health and fertility. Investigating VCD\'s pathogenic mechanisms can offer insights for the prevention of ovarian impairment and the treatment of POI. This study established a mouse model of POI through intraperitoneal injection of VCD into female C57BL/6 mice for 15 days. The results were then compared with those of the control group, including a comparison of phenotypic characteristics and transcriptome differences, at two time points: day 15 and day 30. Through a comprehensive analysis of differentially expressed genes (DEGs), key genes were identified and validated some using RT-PCR. The results revealed significant impacts on sex hormone levels, follicle number, and the estrous cycle in VCD-induced POI mice on both day 15 and day 30. The DEGs and enrichment results obtained on day 15 were not as significant as those obtained on day 30. The results of this study provide a preliminary indication that steroid hormone synthesis, DNA damage repair, and impaired oocyte mitosis are pivotal in VCD-mediated ovarian dysfunction. This dysfunction may have been caused by VCD damage to the primordial follicular pool, impairing follicular development and aggravating ovarian damage over time, making it gradually difficult for the ovaries to perform their normal functions.

This research explored the pathological and molecular mechanisms of 4-vinylcyclohexene diepoxide (VCD)-induced POI model. QRT-PCR was exploited to detect miR-144 expression in the peripheral blood of POI patients. Rat and KGN cells were treated with VCD to construct POI rat or cell model, respectively. After miR-144 agomir or MK-2206 treatment, miR-144 level, follicle damage, autophagy level and expressions of key pathway-related proteins in rats were detected, and cell viability and autophagy in KGN cells were detected. MiR-144 was apparently down-regulated in the peripheral blood of POI patients. Decreased miR-144 was viewed in both the serum and ovary of rats, yet this trend was apparently reversed by miR-144 agomir. The increased concentration of Follicle-stimulating hormone (FSH) and Luteinizing hormone (LH), along with decreased concentration of E2 and AMH, was observed in the serum of model rats, which was conspicuously negated by control agomir or miR-144 agomir. Increased number of autophagosomes, up-regulated PTEN, and inactivated AKT/m-TOR pathway induced by VCD in ovary tissues were strikingly offset by miR-144 agomir. Results of cytotoxicity assay revealed that 2 mM VCD prominently repressed KGN cell viability. In vitro experiments confirmed that miR-144 interfered with the effect of VCD on autophagy in KGN cells through the AKT/mTOR pathway. Taken together, VCD triggers autophagy to induce POI after targeting the AKT pathway by inhibiting miR-144, it suggest that up-regulation the expression of miR-144 may have the potential to treat POI.

4-Vinylcyclohexene diepoxide (VCD) is a potentially hazardous industrial chemical that may enter a goat\'s body in various ways during industrial breeding. Ovarian granulosa cells (GCs) play a critical role in supporting follicle development and hormone synthesis. However, there are few studies on the effect of VCD on goat ovarian GCs. In this study, goat ovarian GCs were isolated and treated with VCD. The results showed that treatment with VCD increased the proportion of S phase and G2/M cells, but decreased the proportion of G1 phase. VCD treatment significantly inhibited the expression of cyclin A and cyclin-dependent kinase 2 (CDK2). But the expression levels of p21 and p27 were increased. VCD could induce an apparent increase in the proportion of apoptosis and the level of cleaved caspase 3. Treatment with VCD significantly reduced the progesterone and estrogen concentration in the medium in which goat ovarian GCs were cultured. Correspondingly, the expression level of steroidogenic acute regulatory protein (STAR) was significantly downregulated. Treatment with 0.25 and 0.5 mM VCD, the protein expression level of insulin-like growth factor 1 receptor (IGF1R) and Akt were significantly decreased. Moreover, treatment with 0.25 mM VCD significantly inhibited the phosphorylation of Akt. In conclusion, VCD exposure had cytotoxic effects such as decreased cell viability, disordered cell cycle, increased apoptosis, and interference with steroid hormone synthesis on goat GCs. These cytotoxic effects of VCD on goat GCs may be due to the downregulation of IGF1R and the inhibition of IGF1R/Akt signaling pathway.

Management of overabundant rodents at a landscape scale is complex but often required to sustainably reduce rodent abundance below damage thresholds. Current conventional techniques such as poisoning are not species specific, with some approaches becoming increasingly unacceptable to the general public. Fertility control, first proposed for vertebrate pest management over 5 decades ago, has gained public acceptance because it is perceived as a potentially more species-specific and humane approach compared with many lethal methods. An ideal fertility control agent needs to induce infertility across one or more breeding seasons, be easily delivered to an appropriate proportion of the population, be species specific with minimal side-effects (behavioral or social structure changes), and be environmentally benign and cost effective. To date, effective fertility control of rodents has not been demonstrated at landscape scales and very few products have achieved registration. Reproductive targets for fertility control include disrupting the hormonal feedback associated with the hypothalamic-pituitary-gonadal axis, gonad function, fertilization, and/or early implantation. We review progress on the oral delivery of various agents for which laboratory studies have demonstrated efficacy in females and/or males and synthesize progress with the development and/or use of synthetic steroids, plant extracts, ovarian specific peptides, and immunocontraceptive vaccines. There are promising results for field application of synthetic steroids (levonorgestrel, quinestrol), chemosterilants (4-vinylcyclohexene diepoxide), and some plant extracts (triptolide). For most fertility control agents, more research is essential to enable their efficient and cost-effective delivery such that rodent impacts at a population level are mitigated and food security is improved.

Women with premature ovarian insufficiency (POI) may be more vulnerable to a variety of health risks. To seek a new method to treat the disease, the effects of low-intensity pulsed ultrasound (LIPUS) on promoting repair of ovarian injury in female SD rats induced by 4-vinylcyclohexene diepoxide (VCD) were explored in this research. A total of 24 female SD rats were subjected to intraperitoneal injection of VCD to induce POI. Successful modeling was achieved in 22 rats, which were then randomized into VCD + LIPUS group (n = 13) and VCD group (n = 9). The control group (n = 5) was injected with equal normal saline. Hematoxylin and eosin staining, enzyme-linked immunosorbent assay, Western blot analysis, scanning electron microscope, immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated nick end labeling assay were applied to detect the results. The results indicated that rats in the VCD group showed disorder in the estrous cycle, the number of atresia follicles and apoptosis granulosa cells increased (p < .05). After the LIPUS treatment, the estrous cycle recovered, the number of follicles increased (p < .05), the level of E2 and anti-Müllerian hormone enhanced (p < .05), and the follicle-stimulating hormone decreased (p < .05). The expression of NF-κB p65, TNFα, Bax, ATF4, and caspase-3 in ovarian tissue was significantly decreased (p < .05). These findings showed that LIPUS could promote the repair of the VCD-induced ovarian damage in SD rats, which has the potential to be further applied in the clinic.

The objective of this study was to compare premature ovarian failure animal models established by several different source of inducers. Female ICR mice, KM mice, and SD rats were treated by cyclophosphamide at 120 mg/kg, busulfan at 12 mg/kg, cisplatin at 3 or 4 mg/kg, 4-vinylcyclohexene diepoxide at 160 mg/kg, 35% galactose food pellet, and tripterygium glycosides at 50 mg/kg, respectively. Parameters were analyzed by body weight, serum concentration level of related hormones, ovarian and uterine pathological examination. The results indicated the body weight of mice increased very slowly following single dose of cyclophosphamide (p < 0.05) with damaged ovary; repeated doses of cisplatin could induce body weight significantly decreased (p < 0.01) with a rising trend of serum LH concentration, declining tendency of serum E2 concentration and injured ovary and uterus; 4-vinylcyclohexene diepoxide also hindered the mice growing (p < 0.05) with damaged ovary and uterus; the body weight of mice feed by 35% galactose food pellet increased slowly (p < 0.05) with dramatically higher serum concentration level of galactose, albumin, and total protein (p < 0.001) and injured ovary. Busulfan and tripterygium glycosides did not present obvious evidences. In conclusion, the inducers presented their respective features in such animal models and should be appropriately applied in preventive methods.