Reproductive Toxicology

Microplastics and gynecological tumors: An emerging environmental health concern

The pervasive environmental contamination by microplastics (MPs) has emerged as a significant threat to human health, with mounting evidence linking exposure to gynecological tumors. This comprehensive review synthesizes current scientific evidence by examining the established risks of chemical additives, exploring the carcinogenic mechanisms of the particles themselves, and highlighting the recent direct detection of MPs in human gynecological tissues. Evidence for this association is multi-faceted: plastic additives such as phthalates and bisphenol A (BPA) are epidemiologically linked to increased cancer risk, while the MP particles themselves are shown to induce pro-carcinogenic responses including oxidative stress, chronic inflammation, and epigenetic changes. Critically, recent studies now confirm the physical presence of MPs within human gynecological tumor tissues, often at higher concentrations than in adjacent normal tissue, strengthening the clinical relevance of these findings. The convergence of chemical, mechanistic, and clinical evidence establishes a compelling case for MP exposure as an emerging risk factor for gynecological malignancies. The findings underscore an urgent need for further research, standardized detection methodologies, and public health strategies to mitigate this environmental threat.

Bisphenol A-induced oxidative stress increases the production of ovarian cancer stem cells in mice

Bisphenol A (BPA) belongs to the endocrine disruptor chemicals (EDCs) causing various reproductive disorders in females. We analysed the toxic effects of BPA in the uterus and ovaries. The BPA was administered orally with the repeated low dose (LD, 1 mg/kg) and high dose (HD, 5 mg/kg) of body weight on alternate days for 4 months via oral gavage to Swiss mice. BPA administration decreases body weight, ovarian weight and size at LD, but increases ovarian weight and size at HD. The uterus weight, length, and diameter were increased in both the treated groups. The histopathological data show decreased ovarian follicle size, epithelial hyperplasia, and lymphocytic infiltration in the ovary. The BPA-treated uterus shows increased vascularization, atrophied endometrium and myometrium, and endometrial hyperplasia (EH) with aberrant glandular growth. The cancer stem cells (CSCs) in the ovaries were identified based on staining with anti-mouse CD44 and anti-mouse CD133 antibodies and analysed by flow cytometry. Three different populations of ovarian CSCs: CD44

Bisphenol-A-induced ovarian cancer: Changes in epithelial diversity, apoptosis, antioxidant and anti-inflammatory mechanisms

This research was designed to study the carcinogenic mechanisms of BPA on ovarian epithelial cells. For four months, mice were treated with low (LD, 1 mg/kg) and high (HD, 5 mg/kg of body weight) doses of BPA on alternate days through oral gavage; the control group was given corn oil through gavaging during 4 months. The histopathological data suggest that repeated BPA administration induces a borderline epithelial neoplasm with altered epithelial morphology with branching papillae. Various epithelial cells (ECs) in ovaries were identified by flow cytometry based on anti-mouse CD74 and podoplanin (PDPL) receptors expression. Three different populations of ovarian epithelial cells were identified: epithelial cells type 1 (PDPL

Unveiling the transcriptional pattern of epithelial ovarian carcinoma-related microRNAs-mRNAs network after mouse exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the most potent organic environmental contaminant known to date, is recognized as a human carcinogen. Despite the documented link between TCDD exposure and epithelial ovarian cancer (EOC) in mammalian females, the molecular mechanisms underlying cancer initiation remain elusive. Emerging evidence suggests aberrant miRNA expression in various human malignancies, including OC. This work was performed to examine whether TCDD exposure in female mice disrupts the expression of miRNAs, particularly those known as OC-modulators. We conducted an extensive search in the PubMed database to identify miRNAs experimentally implicated in OC. Fifty-two miRNAs were identified as potential OC modulators and classified into two groups based on their abundance in OC. Group I comprised 24 miRNAs upregulated in OC, while Group II included 28 miRNAs downregulated in OC. Subsequently, we analyzed the expression of both groups in BALB/c mice ovaries following a single TCDD dose. Our findings revealed significant upregulation of 10 miRNAs from Group I (miR-21, miR-27a, miR-30a, miR-99a, miR-141, miR-182, miR-183, miR-200a, miR-200b, and miR-429) and significant downregulation of 12 miRNAs from Group II (let-7d, miR-15a, miR-19a, miR-23b, miR-34a, miR-34c, miR-125b-1, miR-133, miR-140, miR-199a, miR-210, and miR-383) in TCDD-exposed mouse ovaries. Furthermore, we identified OC-related genes targeted by miRNAs from both groups through an extensive search in PubMed databases. Using TR-qPCR, we evaluated the downstream impact of TCDD-dysregulated miRNAs on their target genes. Our results indicate that TCDD-induced upregulation of oncogenic miRNAs negatively regulates target genes associated with EOC, while downregulation of cancer-suppressor miRNAs positively regulates genes linked to EOC.

Mechanisms of bisphenols-induced cervical cancer: A multidimensional bioinformatics analysis

Bisphenols are widely used industrial chemicals with endocrine-disrupting properties, and their potential association with carcinogenesis has drawn considerable attention. Cervical cancer, as a prevalent gynecological malignancy, has a pathogenesis that is not yet fully understood, particularly regarding the influence of environmental factors. In this study, we systematically investigated the molecular effects of bisphenols on cervical cancer using multi-dimensional bioinformatics approaches. WGCNA analysis identified key modules closely associated with the disease, which were integrated with predicted bisphenols targets to screen for core genes, including AR, CDC25C, CDK2, and KIF11. Functional enrichment analysis suggested that bisphenols may disrupt cell cycle regulation, the G2/M checkpoint, and p53-mediated tumor suppressor pathways. Molecular docking and 100-ns molecular dynamics simulations indicated that various bisphenols can stably bind to core target proteins, with binding patterns influenced by halogenation or aromatic substitutions. Gene expression and immunohistochemical analyses showed that CDC25C, CDK2, and KIF11 were significantly upregulated in cervical cancer tissues, whereas AR was predominantly expressed in normal epithelium. Immune infiltration analysis further suggested that CDC25C, CDK2, and KIF11 may modulate the infiltration of B cells, CD8⁺ T cells, and macrophages, implying that bisphenols-induced molecular perturbations could impact the tumor microenvironment. This study provides a reference for further exploration of the links between environmental exposures and cervical cancer development and lays a foundation for mechanistic investigations.

A mixture of persistent organic pollutants detected in human follicular fluid increases progesterone secretion and mitochondrial activity in human granulosa HGrC1 cells

Disruption of granulosa cells (GCs), the main functional cells in the ovary, is associated with impaired female fertility. Epidemiological studies demonstrated that women have detectable levels of organic pollutants (e.g., perfluorooctanoate, perfluorooctane sulfonate, 2,2-dichlorodiphenyldichloroethylene, polychlorinated biphenyl 153, and hexachlorobenzene) in their follicular fluid (FF), and thus these compounds may directly affect the function of GCs in the ovary. Considering that humans are exposed to multiple pollutants simultaneously, we elucidated the effects of a mixture of endocrine-disrupting chemicals (EDCs) on human granulosa HGrC1 cells. The EDC mixture directly increased progesterone secretion by upregulating 3β-hydroxysteroid dehydrogenase (3βHSD) expression. Furthermore, the EDC mixture increased activity of mitochondria, which are the central sites for steroid hormone biosynthesis, and the ATP content. Unexpectedly, the EDC mixture reduced glucose transporter 4 (GLUT4) expression and perturbed glucose uptake; however, this did not affect the glycolytic rate. Moreover, inhibition of GLUT1 by STF-31 did not alter the effects of the EDC mixture on steroid secretion but decreased basal estradiol secretion. Taken together, our results demonstrate that the mixture of EDCs present in FF can alter the functions of human GCs by disrupting steroidogenesis and may thus adversely affect female reproductive health. This study highlights that the EDC mixture elicits its effects by targeting mitochondria and increases mitochondrial network formation, mitochondrial activity, and expression of 3βHSD, which is associated with the inner mitochondrial membrane.

MiR-193a-5p serves as an inhibitor in ovarian cancer cells through RAB11A

Ovarian cancer is often not diagnosed until it is in advanced stages and its cure rate is relatively low. Thus, this investigation is concerned about the pathogenesis of this cancer. Differential expression analysis was undertaken on messenger RNA (mRNA) and microRNA (miRNA) data of ovarian cancer in Gene Expression Profiling Interactive Analysis and Gene Expression Omnibus databases. RAB11A mRNA and miR-193a-5p expression levels were tested by quantitative polymerase chain reaction. The targeting relationship between RAB11A and miR-193a-5p was verified by dual-luciferase assay. Cell behaviors of ovarian cancer were tested by Cell-Counting-Kit-8, colony formation and transwell assays. Expression of RAB11A protein and the proteins associated with Wnt/β-catenin was tested by western blot. RAB11A high expression and miR-193a-5p low expression were found in ovarian cancer cells. RAB11A was targeted by miR-193a-5p. Cellular function experiments proved that RAB11A facilitated Wnt/β-catenin signaling activation and deteriorated ovarian cancer progression. Rescue experiments exhibited two results: miR-193a-5p hindered proliferation, migration and invasion of ovarian cancer cells, and this suppression was counteracted by overexpression of RAB11A and miR-193a-5p. Furthermore, miR-193a-5p repressed RAB11A-mediated Wnt/β-catenin activation. Altogether, miR-193a-5p served as a modulator in ovarian cancer cells via targeting RAB11A.

MicroRNA-20a-5p inhibits the autophagy and cisplatin resistance in ovarian cancer via regulating DNMT3B-mediated DNA methylation of RBP1

Ovarian cancer (OvCa) is the third most common female malignancy worldwide and poses great threats on women health. Chemotherapy is the most recommended post-surgery treatment for OvCa patients; but, cisplatin resistance is a main cause of chemotherapy failure. In addition, autophagy modulates the sensitivity of tumor cells to chemotherapeutic agents. Hence, it is significant to explore the molecular mechanism concerning the autophagy and cisplatin resistance in OvCa. In this study, quantitative real-time PCR (qRT-PCR) was used to detect miR-20a-5p expression and western blot to measure RBP1 expression. A series of assays were conducted to explore the gain-of-function effects of miR-20a-5p. Luciferase reporter assay was applied to determine the downstream target of miR-20a-5p. The results proved that miR-20a-5p represses malignant phenotypes and autophagy in cisplatin-resistant OvCa cells. In addition, DNMT3B mediates DNA methylation of RBP1 to impair the promoting effects of RBP1 on carcinogenesis and autophagy in OvCa. Through rescue experiments, we certified that miR-20a-5p inhibits the autophagy and cisplatin resistance in OvCa via DNMT3B-mediated DNA methylation of RBP1. Collectively, we demonstrated that miR-20a-5p plays a crucial role in the modulation of autophagy and cisplatin resistance in OvCa, which might offer novel insights into developing effective treatment strategies for OvCa.