Journal of Hazardous Materials

TBBPA stimulated cell migration of endometrial cancer via the contribution of NOX-generated ROS in lieu of energy metabolism

Due to the extensive applications and deleterious effects of Tetrabromobisphenol A (TBBPA), the health risk and possible mechanisms have been a topic of concern. However, the knowledge on carcinogenic risk of TBBPA and corresponding mechanisms remains scarce. In this study, endometrial cancer cells were exposed to low doses of TBBPA and its main derivatives including TBBPA bis (2,3-dibromopropyl ether) (TBBPA-BDBPE) and TBBPA bis (2-hydroxyethyl ether) (TBBPA-BHEE). The data from wound healing and transwell assays demonstrated that TBBPA treatment exhibited the strongest enhanced effect on cell migration among other tested treatments. Of note, the process of invasion rather than epithelial-mesenchymal transition (EMT) was accompanied by the occurrence of migration elevated by TBBPA. Furthermore, the levels of several metabolite indicators were measured to assess the underlying mechanisms involved in TBBPA-induced cell migration. The findings suggested that NADPH oxidase (NOX)-driven ROS instead of energy metabolism was sensitive to TBBPA stimulation. In addition, molecular docking supported a link between TBBPA ligand and NOX receptor. Accordingly, this study has provided new insights for TBBPA-induced carcinogenic effects and may arise peoples' vigilance to environmental pollution of brominated flame retardant.

Microplastic changes during the development of cervical cancer and its effects on the metabolomic profiles of cancer tissues

Recent studies have detected microplastics (MPs) in reproductive organs and found that they exert toxic effects on the reproductive system. However, the exact mechanism of action remains unclear. This study evaluates changes in MP levels in patients with cervical cancer as the disease progresses and uses untargeted metabolomics to assess the impact of MP exposure on the metabolomic profiles of cervical invasive cancer tissues. A total of 12 MP types were identified in 101 MP particles, with an average abundance of 2.24 ± 1.61 MP particles/g. Of these, polyethylene (PE, 26.73 %) and polypropylene (PP, 19.80 %) were the most frequently detected. Also, some MPs were observed to have sizes smaller than 20 µm. Notably, MP exposure levels increase as cervical cancer progresses (p < 0.05). Metabolomics analysis revealed that, among the 33 biologically significant metabolites screened, D-Mannose and cis,cis-muconic acid showed the most significant differences. Additionally, the aminosugar and nucleotide sugar metabolism pathways were the most significantly enriched in this experiment, potentially acting as pathways through which MPs may contribute to the pathogenesis of cervical cancer. The metabolites and pathways identified in this study may offer new insights and opportunities for disease research in patients with cervical cancer.

Bisphenols exposure at environmentally relevant dose promoted ovarian cancer progression and modulated tumor microenvironment through β-catenin/SPP1 axis

Bisphenol A (BPA) and its substitute, Bisphenol S (BPS) are typical endocrine-disrupting chemicals used in plastics, but their cancer-promoting effect has remained controversial. Here, we investigated the effects of environmentally relevant doses of BPA/BPS exposure on the tumor microenvironment (TME) in ovarian cancer. BPA exposure levels was exhibiting a declining trend and BPS showing an ascending trend in the female population by analyzing the NHANES data (2013-2016). Low doses of BPA/BPS both significantly promoted the migration and invasion of ovarian cancer cells in a dose-dependent manner by activating the Wnt/β-catenin signaling pathway, thereby facilitating the SPP1 gene transcription. Notably, low-dose BPA/BPS exposure stimulated ovarian cancer cells to secrete OPN protein (coded by the SPP1 gene), subsequently inducing the transformation of fibroblasts into cancer-associated fibroblasts (CAFs), which could reshape the TME of ovarian cancer. Two in-vivo experiments established with nude mice and SPP1

Different co-culture models reveal the pivotal role of TBBPA-promoted M2 macrophage polarization in the deterioration of endometrial cancer

Tetrabromobisphenol A (TBBPA), an emerging organic pollutant widely detected in human samples, has a positive correlation with the development of endometrial cancer (EC), but its underlying mechanisms have not yet been fully elucidated. Tumor-associated macrophages (TAM), one of the most vital components in tumor microenvironment (TME), play regulatory roles in the progression of EC. Consequently, this study mainly focuses on the macrophage polarization in TME to unveil the influence of TBBPA on the progression of EC and involved mechanisms. Primarily, low doses of TBBPA treatment up-regulated M2-like phenotype biomarkers in macrophage. The data from in vitro co-culture models suggested TBBPA-driven M2 macrophage polarization was responsible for the EC deterioration. Results from in vivo study further confirmed the malignant proliferation of EC promoted by TBBPA. Mechanistically, TBBPA-mediated miR-19a bound to the 3'-UTR regions of SOCS1, resulting in down-regulation of SOCS1 followed by the phosphorylation of JAK and STAT6. The present study not only revealed for the first time the molecular mechanism of TBBPA-induced EC's deterioration based on macrophage polarization, but also established co-culture models, thus providing a further evaluation method for the exploration of environmental pollutants-induced tumor effects from the role of TME.

Long-term 4-nonylphenol exposure drives cervical cell malignancy through MAPK-mediated ferroptosis inhibition

4-NP (4-nonylphenol), a prevalent environmental endocrine disruptor with estrogenic properties, is commonly detected in drinking water and food sources. It poses a significant risk of endocrine disruption, thereby influencing the onset and progression of diverse diseases, including tumorigenesis. However, its specific impact on cervical cancer remains to be fully elucidated. Our study focused on the biological effects of sustained exposure to low-dose 4-NP on human normal cervical epithelial cells (HcerEpic). After a continuous 30-week exposure to 4-NP, the treated cells exhibited a significant malignant transformation, whereas the solvent control group showed limited malignant phenotypes. Subsequent analyses of the metabolomic profiles of the transformed cells unveiled marked irregularities in glutathione metabolism and unsaturated fatty acid metabolism. Analyses of transcriptomic profiles revealed significant activation of the MAPK signaling pathway and suppression of ferroptosis processes in these cells. Furthermore, the expression of MT2A was significantly upregulated following 4-NP exposure. Knockdown of MT2A restored the aberrant activation of the MAPK signaling pathway, elevated antioxidant capacity, ferroptosis inhibition, and ultimately the development of malignant phenotypes that induced by 4-NP in the transformed cells. Mechanistically, MT2A increased cellular antioxidant capabilities and facilitated the removal of toxic iron ions by enhancing the phosphorylation of ERK1/2 and JNK MAPK pathways. The administration of activators and inhibitors of the MAPK pathway confirmed that the MAPK pathway mediated the 4-NP-induced suppression of ferroptosis and, ultimately, the malignant transformation of cervical epithelial cells. Overall, our findings elucidated a dynamic molecular transformation induced by prolonged exposure to 4-NP, and delineated comprehensive biological perspectives underlying 4-NP-induced cervical carcinogenesis. This offers novel theoretical underpinnings for the assessment of the carcinogenic risks associated with 4-NP.

Induction of fibrosis following exposure to bisphenol A and its analogues in 3D human uterine leiomyoma cultures

Bisphenol A (BPA) and its analogues (BPAF, BPS) are ubiquitous environmental contaminants used as plastic additives in various daily life products, with many concerns on their role as environmental estrogens. Uterine leiomyomas (fibroids) are highly prevalent gynecologic tumors with progressive fibrosis. Fibroids are hormone-responsive and may be the target of environmental estrogens. However, the effects of BPA, BPAF, and BPS exposure on uterine fibrosis are largely unknown. Here, we evaluated fibrosis and the crucial role of TGF-beta signaling in human fibroid tumors, the profibrotic effects of BPA, BPAF or BPS in a human 3D uterine leiomyoma (ht-UtLM) in vitro model, and the long-term outcomes of BPAF exposure in rat uterus. In 3D ht-UtLM spheroids, BPA, BPAF, and BPS all promoted cell proliferation and fibrosis by increasing the production of extracellular matrices. Further mechanistic analysis showed the profibrotic effects were induced by TGF-beta signaling activation mainly through SMAD2/3 pathway and crosstalk with multiple non-SMAD pathways. Furthermore, the profibrotic effects of BPAF were supported by observation of uterine fibrosis in vivo in rats following long-term BPAF exposure. Overall, the 3D ht-UtLM spheroid can be an important model for investigating environment-induced fibrosis in uterine fibroids. BPA and its analogues can induce fibrosis via TGF-beta signaling.