Findings demonstrate that subchronic Cd exposure promotes RCC cell proliferation in vitro and highlight Cd as a relevant environmental modifier of RCC progression and underscore the need for further investigation into its clinical implications for metastasis and disease management via in vivo mouse models currently in development.
Abstract
As of 2025, kidney cancer is the seventh most common cancer according to the National Institutes of Health. Renal cell carcinoma (RCC), the predominant form of kidney cancer, has been linked to environmental exposures, including toxic metals. Cadmium (Cd), a widespread environmental contaminant associated with multiple adverse health effects, enters the body primarily through smoking, diet, or occupational exposure. Elevated blood Cd levels have been observed in RCC patients, and meta-analyses of observational studies have established a positive association between Cd exposure and increased RCC risk. Evidence from previous studies further suggests that Cd may modulate proteins involved in the epithelial-to-mesenchymal transition (EMT), a key process in cancer progression and metastasis. To explore the role of Cd in RCC progression, we examined the effects of subchronic Cd exposure on Renca cells, a murine RCC cell line. Cells were treated with 0.5 µM Cd for one passage (acute exposure) or 10–21 passages (subchronic exposure). We assessed cell proliferation, colony formation, and protein/gene expression via Western blotting and qPCR. Subchronic Cd exposure significantly enhanced proliferation and colony formation in Renca cells compared to controls. It also upregulated estrogen receptor alpha (ER[alpha]) gene expression, consistent with Cd's known metalloestrogenic activity. Conditioned medium from Cd challenged cells stimulated proliferation in untreated control cells, indicating activation of an autocrine growth-promoting pathway. Additionally, acute exposure to Cd reduced E-cadherin expression, a hallmark of EMT induction. These findings demonstrate that subchronic Cd exposure promotes RCC cell proliferation in vitro. Potential underlying mechanisms include elevated ER[alpha] and TGF-[beta] signaling, which may contribute to enhanced metastatic potential via EMT. These results highlight Cd as a relevant environmental modifier of RCC progression and underscore the need for further investigation into its clinical implications for metastasis and disease management via in vivo mouse models currently in development.
Ambient fine particulate matter (PM2.5) is an established environmental health hazard, but its role in clear cell renal cell carcinoma (ccRCC) progression remains incompletely understood. This study integrated epidemiological analysis, mechanistic experiments, transcriptomic profiling, and clinical tissue validation to investigate the association between ambient PM2.5 exposure and ccRCC aggressiveness. Among 1410 patients with pathologically confirmed ccRCC, long-term residential PM2.5 exposure during the 36 months before diagnosis was estimated using geocoded addresses and the Tracking Air Pollution in China dataset. Each 10 μg/m3 increase in PM2.5 exposure was independently associated with advanced AJCC stage (adjusted OR, 1.42; 95% CI, 1.15-1.74) and higher WHO/ISUP grade (adjusted OR, 1.36; 95% CI, 1.12-1.65). Locally collected winter ambient PM2.5 exhibited irregular morphology, heterogeneous aggregation, and complex chemical composition. In vitro and in vivo, PM2.5 enhanced ccRCC cell proliferation, clonogenic growth, migration, invasion, epithelial-mesenchymal transition-like remodeling, and tumor growth. Mechanistically, PM2.5 increased intracellular and mitochondrial ROS, activated PI3K/AKT signaling, enhanced HIF-2α protein stability and nuclear accumulation, and increased HIF-related transcriptional output. Complementary antioxidant, pharmacological, genetic, and rescue experiments supported a functional contribution of the ROS/AKT/HIF-2α axis to PM2.5-associated malignant phenotypes. Transcriptomic profiling identified ROS-responsive genes enriched in oxidative stress, PI3K/AKT signaling, hypoxia response, extracellular matrix organization, and EMT-related pathways. PM2.5 also activated NF-κB-related inflammatory signaling, suggesting an additional ROS-responsive inflammatory response. Clinical ccRCC tissues from patients with higher PM2.5 exposure showed increased HIF-2α and Ki-67 expression together with EMT-related protein alterations. Collectively, these findings indicate that long-term ambient PM2.5 exposure is associated with more aggressive ccRCC and support a model in which oxidative stress contributes, at least in part, to tumor progression through AKT/HIF-2α signaling.
Chronic Kidney Disease (CKD) represents a significant global health burden, characterized by a progressive decline in renal function. While traditional risk factors such as diabetes and hypertension are well-established, the role of environmental pollutants, particularly heavy metals, in the etiology and progression of CKD is gaining increasing attention. This comprehensive review synthesizes current knowledge on the impact of heavy metal exposure on CKD, with a specific focus on findings from the Southern Tamil Nadu population. It delvesinto the mechanisms by which various heavy metals, including but not limited to arsenic, lead, cadmium, and mercury, exert nephrotoxic effects, leading to cellular damage, glomerulosclerosis, and impaired renal function. The review also examines the prevalence of heavy metal exposure in susceptible populations, routes of exposure, and the challenges in establishing clear causal links due to the heterogeneity of environmental factors and population demographics. Furthermore, it discusses diagnostic approaches, potential therapeutic interventions, and the critical need for effective management strategies to mitigate the adverse health outcomes associated with heavy metal-induced nephropathy. By integrating findings from recent studies and highlighting the uniquecontext of Southern Tamil Nadu, this review aims to provide a deeper understanding of this complex public health issue and underscore the importance of environmental monitoring and public health interventions to prevent and manage CKD.
Balasubramanian. J, A. G. Murugesan· Asian Journal of Medical Res...· 0 citations
The increasing global use of organophosphate esters (OPEs) has raised concerns about their environmental and health impacts, with evidence suggesting adverse effects on reproductive system health. As a widely used OPE, triphenyl phosphate (TPHP) has drawn attention for its endocrine-disrupting properties; however, its effects on cervical epithelial cells and association with cervical diseases remain unclear. In this study, analysis of 12 urinary OPE metabolites (mOPEs) in 116 cervical cancer (CC) cases and 116 controls revealed that multiple exposure biomarkers, particularly those related to TPHP exposure, were significantly positively associated with CC risk, suggesting a potential link between OPE exposure and disease development. In toxicological experiments, acute exposure to TPHP (50 μM, 24 h) induced significant cytotoxicity in human cervical epithelial cells (HcerEpic), characterized by reduced cell viability, cell cycle disruption, apoptosis, and oxidative stress. Conversely, chronic low-dose exposure (100 nM, 30 weeks) conferred a survival advantage to HcerEpic cells and enhanced their epithelial-mesenchymal transition (EMT) capacity, with enhanced tumor formation ability observed in a nude mouse xenograft model. Transcriptomic analysis revealed that ferroptosis was a significantly enriched pathway in both exposure models. Furthermore, experimental validation confirmed that acute TPHP exposure induced ferroptosis in HcerEpic cells, whereas chronically exposed cells exhibited ferroptosis resistance. Collectively, our findings highlight the critical role of ferroptosis dysregulation in TPHP-induced acute and chronic toxicities in HcerEpic cells, suggesting that TPHP may be a potential risk factor for CC and underscoring the need for further attention to the health risks associated with OPE exposure.
Yamei Nie, Shizhi Wang, Wei Sun et al.· Journal of Applied Toxicolog...· 0 citations
Renal cell carcinoma (RCC) is a heterogeneous malignancy for which clear cell RCC (ccRCC) represents the most common and clinically aggressive subtype. Survivin (encoded by BIRC5), an inhibitor of apoptosis and key regulator of mitosis, is frequently overexpressed in RCC and associated with poor prognosis, yet its broader role in kidney cancer biology remains poorly defined. By analyzing transcriptomic data from The Cancer Genome Atlas-kidney renal clear cell carcinoma (TCGA-KIRC) cohort, we found that advanced-stage ccRCC exhibits widespread dysregulation of cell-cycle pathways, with 15,160 genes upregulated and 479 genes downregulated in stage IV compared to stage I tumors. To define survivin's functional contribution, we performed loss-of-function and pharmacologic inhibition studies in murine RENCA and human 786-O RCC cell lines. Survivin knockdown or treatment with the small-molecule inhibitor YM155 reduced proliferation, S-phase entry and cyclin D1 expression, and impaired collective (wound-healing), single-cell and transwell migration. Unexpectedly, survivin depletion increased mitochondrial content while lowering oxygen consumption, indicating accumulation of dysfunctional mitochondria. Together, these findings identify survivin as a node between cell-cycle progression and mitochondria in RCC.
S. Tuli, Gabrielle Inserra, Yamato Murakami et al.· Disease Models & Mechanisms· 0 citations
Overall, evidence linking BPA exposure to ovarian-cancer-related outcomes remains limited, and current findings do not establish that BPA causes OC or worsens patient prognosis in humans.
Lu-Lu Zhang, Tong Yu, Zhong-Liu Bian et al.· Frontiers in Cell and Develo...· 0 citations
People around the globe are affected by extensive environmental and occupational exposure to heavy metals, which poses a significant threat to various health hazards, with cancer being a major concern. These toxic metals are ubiquitously found in food, air, water, and industrial, agricultural, or pharmaceutical applications. Being non-biodegradable, they accumulate in the living organism. The prolong exposure to these metals can result into hazardous effects in the many organs including respiratory problems, gastrointestinal disorders, renal issues, and skin lesions etc. Arsenic (As), Cadmium (Cd), Chromium (Cr), Nickel (Ni), Mercury (Hg), and Lead (Pb) are the most common heavy metals causing carcinogenicity through both genetic and epigenetic mechanisms. The literature indicates that DNA damage, deregulation of gene expression, interference with cell signaling, etc., contribute to metal-induced carcinogenesis. Changes in epigenetic processes, such as DNA methylation, histone modification, chromatin remodeling, and non-coding RNAs, can disturb normal cell function and may even lead to cancer. However, the molecular mechanism remains poorly understood. Advancements in the field have underscored the critical roles of genetic mutations and epigenetic modifications in metal-induced tumor formation. This review gives a comprehensive overview of the function of metals in causing cancer, focusing on pathways such as genotoxicity, mutagenesis, epigenetic modification, and cancer-related signaling. Furthermore, with the ultimate goal of reducing the burden of this disease, the targeted preventive strategies, such as reducing the emission of these toxic metals into the environment from mining to industries, or other sources, and the need for social interventions, have been discussed.
Shipra Singh, Priyanka Phogat, Luciano Saso et al.· Frontiers in Oncology· 0 citations
