Urinary arsenic speciation and metabolic indices associate with exposure chemistry and prostate cancer aggressiveness

Background: Prostate cancer (PCa) is the second most common type of cancer among men worldwide. Environmental exposure to arsenic has been implicated in PCa carcinogenesis and progression through various pathways. This study assessed arsenic species and methylation indices and their association with aggressive PCa. Methods: We analyzed data from 1,497 men (722 Black and 775 White) enrolled in the North Carolina-Louisiana Prostate Cancer Project (PCaP), including 396 with high and 1,101 with low aggressive PCa. Urinary arsenic species concentrations were quantified using HPLC-ICPMS and adjusted for urine dilution using creatinine. We assessed the arsenic species including inorganic arsenic (iAs), monomethylarsonate (MMA), and dimethylarsinate (DMA) and methylation indices (Primary Methylation Index and Secondary Methylation Index) between low vs. high aggressive groups using univariable tests. We also performed multivariable logistic regression models, adjusting for screening history, waist-to-hip ratio (WHR), age, smoking status, study site and race. Results: Univariable comparisons showed no significant difference in individual arsenic species and methylation indices with low vs. high aggressive PCa (all p>0.10). However, median concentrations of total inorganic arsenic (iAs+DMA+MMA) showed a marginal difference between low vs. high aggressive PCa (1.34[0.39-2.68] vs. 1.49[0.62-3.02], p=0.06). When comparing race, Black and White men had similar levels of total iAs (1.35[0.42-2.86] vs. 1.39[0.46-2.68]; p=0.83). Multivariable logistic regression models showed overall positive association with elevated arsenic concentrations, with tertile 2 and 3 showing significantly higher odds of aggressive PCa (OR: 1.39, 95% CI: 1.01-1.91, p = 0.04 and OR: 1.45, 95%CI: 1.07-1.97, p = 0.02, respectively). A significant linear trend was also observed across increasing total iAs tertiles (p-trend=0.02). Race-stratified models showed significant association for White men (OR: 1.68, 95% CI: 1.05-2.67, p = 0.03) and not statistically significant association for Black men (OR: 1.34, 95% CI: 0.89-2.03, p = 0.16). Race did not modify the association between total iAs and aggressive PCa (p-interaction = 0.76). PMI and SMI were not significantly associated with aggressive PCa in adjusted models (OR: 1.01, 95% CI: 0.81-1.25, p = 0.91; and OR: 1.13, 95% CI: 0.96-1.33, p = 0.14). Conclusions: Our findings show that elevated urinary inorganic arsenic levels are associated with increased odds of aggressive prostate cancer, independent of race and methylation efficiency. The results point to inorganic arsenic, rather than its methylated metabolites, as the key chemical driver of prostate cancer progression. This connection between arsenic speciation and prostate cancer aggressiveness underscores the translational importance of environmental chemistry in cancer prevention.