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Background: Agricultural work and occupational pesticide use have been associated with increased risk of renal cell carcinoma (RCC), the most common form of kidney cancer. However, few prospective studies have investigated links to specific pesticides. Objective: We evaluated the lifetime use of individual pesticides and the incidence of RCC. Methods: We evaluated the associations between intensity-weighted lifetime days (IWDs) of 38 pesticides and incident RCC in the Agricultural Health Study, a prospective cohort of licensed pesticide applicators in Iowa and North Carolina. Among 55,873 applicators, 308 cases were diagnosed between enrollment (1993–1997) and the end of follow-up (2014–2015). We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) using Poisson regression, controlling for potential confounding factors, with lagged and unlagged pesticide exposures. Results: There was a statistically significant increased risk of RCC among the highest users of 2,4,5-T compared with never users [unlagged RRIWD Tertile 3=2.92 (95% CI: 1.65, 5.17; ptrend=0.001)], with similar risk estimates for lagged exposure [20-y lag RRIWD Tertile 3=3.37 (95% CI: 1.83, 6.22; ptrend=0.001)]. In 20-y lagged analyses, we also found exposure–response associations with chlorpyrifos [RRIWD Quartile 4=1.68 (95% CI: 1.05, 2.70; ptrend=0.01)], chlordane [RRIWD Tertile 3=2.06 (95% CI: 1.10, 3.87; ptrend=0.02)], atrazine [RRIWD Quartile 4=1.43 (95% CI: 1.00, 2.03; ptrend=0.02)], cyanazine [RRIWD Quartile 4=1.61 (95% CI: 1.03, 2.50; ptrend=0.02)], and paraquat [RRIWD>Median=1.95 (95% CI: 1.03, 3.70; ptrend=0.04)]. Conclusions: This is, to our knowledge, the first prospective study to evaluate RCC risk in relation to various pesticides. We found evidence of associations with RCC for four herbicides (2,4,5-T, atrazine, cyanazine, and paraquat) and two insecticides (chlorpyrifos and chlordane). Our findings provide insights into specific chemicals that may influence RCC risk among pesticide applicators. Confirmation of these findings and investigations of the biologic plausibility and potential mechanisms underlying the observed associations are warranted. https://doi.org/10.1289/EHP6334

Background: The tumor microenvironment plays an important role in the progression of cancer by mediating stromal–epithelial paracrine signaling, which can aberrantly modulate cellular proliferation and tumorigenesis. Exposure to environmental toxicants, such as inorganic arsenic (iAs), has also been implicated in the progression of prostate cancer. Objective: The role of iAs exposure in stromal signaling in the tumor microenvironment has been largely unexplored. Our objective was to elucidate molecular mechanisms of iAs-induced changes to stromal signaling by an enriched prostate tumor microenvironment cell population, adipose-derived mesenchymal stem/stromal cells (ASCs). Results: ASC-conditioned media (CM) collected after 1 week of iAs exposure increased prostate cancer cell viability, whereas CM from ASCs that received no iAs exposure decreased cell viability. Cytokine array analysis suggested changes to cytokine signaling associated with iAs exposure. Subsequent proteomic analysis suggested a concentration-dependent alteration to the HMOX1/THBS1/TGFβ signaling pathway by iAs. These results were validated by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) and Western blotting, confirming a concentration-dependent increase in HMOX1 and a decrease in THBS1 expression in ASC following iAs exposure. Subsequently, we used a TGFβ pathway reporter construct to confirm a decrease in stromal TGFβ signaling in ASC following iAs exposure. Conclusions: Our results suggest a concentration-dependent alteration of stromal signaling: specifically, attenuation of stromal-mediated TGFβ signaling following exposure to iAs. Our results indicate iAs may enhance prostate cancer cell viability through a previously unreported stromal-based mechanism. These findings indicate that the stroma may mediate the effects of iAs in tumor progression, which may have future therapeutic implications. Citation: Shearer JJ, Wold EA, Umbaugh CS, Lichti CF, Nilsson CL, Figueiredo ML. 2016. Inorganic arsenic–related changes in the stromal tumor microenvironment in a prostate cancer cell–conditioned media model. Environ Health Perspect 124:1009–1015; http://dx.doi.org/10.1289/ehp.1510090