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Background: A growing number of studies link chronic exposure to inorganic arsenic (iAs) with the risk of diabetes. Many of these studies assessed iAs exposure by measuring arsenic (As) species in urine. However, this approach has been criticized because of uncertainties associated with renal function and urine dilution in diabetic individuals., Objectives: Our goal was to examine associations between the prevalence of diabetes and concentrations of As species in exfoliated urothelial cells (EUC) as an alternative to the measures of As in urine., Methods: We measured concentrations of trivalent and pentavalent iAs methyl-As (MAs) and dimethyl-As (DMAs) species in EUC from 374 residents of Chihuahua, Mexico, who were exposed to iAs in drinking water. We used fasting plasma glucose, glucose tolerance tests, and self-reported diabetes diagnoses or medication to identify diabetic participants. Associations between As species in EUC and diabetes were estimated using logistic and linear regression, adjusting for age, sex, and body mass index., Results: Interquartile-range increases in trivalent, but not pentavalent, As species in EUC were positively and significantly associated with diabetes, with ORs of 1.57 (95% CI: 1.19, 2.07) for iAsIII, 1.63 (1.24, 2.15) for MAsIII, and 1.31 (0.96, 1.84) for DMAsIII. DMAs/MAs and DMAs/iAs ratios were negatively associated with diabetes (OR = 0.62; 95% CI: 0.47, 0.83 and OR = 0.72; 95% CI: 0.55, 0.96, respectively)., Conclusions: Our data suggest that uncertainties associated with measures of As species in urine may be avoided by using As species in EUC as markers of iAs exposure and metabolism. Our results provide additional support to previous findings suggesting that trivalent As species may be responsible for associations between diabetes and chronic iAs exposure.

Inorganic arsenic (iAs) is a well-established carcinogen and human exposure has been associated with a variety of cancers including those of skin, lung, and bladder. High expression of transforming growth factor alpha (TGF-alpha) has associated with local relapses in early stages of urinary bladder cancer. iAs exposures are at least in part determined by the rate of formation and composition of iAs metabolites (MAs(III), MAs(V), DMAs(III), DMAs(V)). This study examines the relationship between TGF-alpha concentration in exfoliated bladder urothelial cells (BUC) separated from urine and urinary arsenic species in 72 resident women (18-51 years old) from areas exposed to different concentrations of iAs in drinking water (2-378 ppb) in central Mexico. Urinary arsenic species, including trivalent methylated metabolites were measured by hydride generation atomic absorption spectrometry method. The concentration of TGF-alpha in BUC was measured using an ELISA assay. Results show a statistically significant positive correlation between TGF-alpha concentration in BUC and each of the six arsenic species present in urine. The multivariate linear regression analyses show that the increment of TGF-alpha levels in BUC was importantly associated with the presence of arsenic species after adjusting by age, and presence of urinary infection. People from areas with high arsenic exposure had a significantly higher TGF-alpha concentration in BUC than people from areas of low arsenic exposure (128.8 vs. 64.4 pg/mg protein; p<0.05). Notably, exfoliated cells isolated from individuals with skin lesions contained significantly greater amount of TGF-alpha than cells from individuals without skin lesions: 157.7 vs. 64.9 pg/mg protein (p=0.003). These results suggest that TGF-alpha in exfoliated BUC may serve as a susceptibility marker of adverse health effects on epithelial tissue in arsenic-endemic areas.