Tens of millions of people worldwide have been chronically exposed to arsenic-contaminated drinking water with the arsenic concentrations exceeding the WHO recommended level of 0.01 mg/L. Chronic environmental exposure to arsenic through drinking water is reported to be possibly associated with the elevated risks of hypertension and other cardiovascular diseases [20–22]. Up to date, only a few cross-sectional and cohort studies, mainly from Taiwan, Bangladesh and the United States, have investigated the association between hypertension and chronic arsenic exposure, however, it is still inconclusive [15, 16]. Most of the reports have discussed the association from the point of view of arsenic concentration in the drinking water or CAE, few involved arsenic speciation into the discussion. In this study, we evaluated the potential association between environmental arsenic exposure through drinking water and the prevalence of hypertension by analyzing not only CAE but also urinary arsenic speciation, and provided data on arsenic exposure and hypertension from mainland of China.
In this study, we did not find any significant differences of urinary arsenic percentage between subjects with and without hypertension. The urinary concentration of arsenic species of iAs, MMA, DMA and tAs of subjects with hypertension were significantly higher than those of the subjects without hypertension. Besides, significant positive correlations were found between the concentration of urinary arsenic species (iAs, MMA, DMA and tAs) and blood pressure (systolic and pulse blood pressure). However, no significant differences were found between urinary arsenic percentage and blood pressure. These results suggested that the urinary concentration of arsenic species was associated with the elevated blood pressure, which indicated the possible role of arsenic in the development of arsenic-induced hypertension.
Since the levels of urinary arsenic species were dependent on the cumulative body burden of arsenic exposure, the higher cumulative arsenic burden, the higher urinary arsenic species. Our further findings of the positive association between CAE and hypertension in the subjects of the highest tertile of CAE, and the positive trend of increasing risk of hypertension in corresponding to increasing level of CAE indicated that the cumulative arsenic burden, which was demonstrated by urinary arsenic species, was associated with hypertension, and that there was a strong linkage between high level of CAE and the risk of hypertension.
Among the urinary arsenic species of iAs, MMA, DMA and tAs, we found that subjects with higher urinary concentration of MMA tended to be liable to suffer from hypertension with a significant dose-dependent trend. Besides, subjects with lower percentage of urinary DMA also showed an elevated susceptibility to hypertension. Since DMA was the methylated metabolite of MMA, lower percentage of DMA implied less production of DMA from MMA, which resulted in MMA remaining unmethylated and accumulated.
MMA, the intermediate metabolites of arsenic methylation, is more reactive and toxic than the other arsenic species, especially MMAIII. It has been reported that the urinary level of MMAIII, which is the most toxic species among identified metabolites of iAs, may serve as an indicator to identify individuals with increased susceptibility to toxic and cancer-promoting effects of arsenicosis . Many researches including our previous studies indicated that high concentration or percentage of MMA in the urine was associated with arsenic-related skin lesions and cancers [19, 24–26]. Our findings in this study suggested that higher concentration of urinary MMA might be related to the increased susceptibility to hypertension, one of the noncancerous diseases of arsenicosis. The MMA detected in this study included both the trivalent and pentavalent forms. We couldn’t detect the single concentration of MMAIII in the urine due to the undeveloped analysis system in our laboratory. It is obvious that the higher concentration of MMA in the urine, the higher level of MMAIII produced during the methylation pathway. Therefore, concentration of urinary MMA could be considered as a marker of MMAIII converted, although it is not direct. Our findings are quite compatible with the Huang group’s study which showed that subjects with hypertension had a higher CAE and a higher percentage of urinary pentavalent MMA (MMAV) than the subjects without hypertension in the arsenicosis-hyperendemic areas in southwest of Taiwan where residents stopped drinking the artesian well water for 2 to 3 decades .
Since MMAIII is the most reactive and toxic metabolite of arsenicals, recent studies have focused on the role of it on the mechanisms of arsenic-related cancer and noncancerous diseases. It has been reported that MMAIII could induce smooth muscle dysfunction through the disturbance of Ca2+ regulation, which resulted in impaired vasoconstriction and aberrant blood pressure change . Lim et al. further indicated that low concentrations of MMAIII at nanomolar level could potentiate the agonist-induced vasoconstriction through Rho-mediated Ca2+ sensitization, which was manifested in vivo as increased pressor responses leading to dysregulation of normal physiological hemodynamics . Our pervious study also found that MMAIII induced endothelial nitric oxide synthase (eNOS) phosphorylation in the endothelial cells which seemed to be an adaptive response at the early stage of exposure, but finally acted as a potent inhibitor of eNOS leading to disruption of eNOS bioactivity which consequently resulted in decreased NO bioactivity . All of these studies provided evidences for the role of MMAIII in arsenic-associated cardiovascular disease of hypertension.
Because the participants of this study were recruited from a rural county in which residents almost had the same occupation as farmers, similar socioeconomic status and lifestyles, the variation among subjects of these potential confounders is likely to be small. Whereas dietary habits, such as salt intake and dietary pattern, might have an effect on the result. The lack of data collection on salt intake, which has been considered as a potential cause of hypertension, was a limitation of this study. Since low intake of calcium, animal protein, folate, and fiber were reported to increase the susceptibility of arsenic-related injuries , and some vitamins, especially folic acid, was found to act as the co-factors in the methylation metabolism of arsenic leading to variation of arsenic speciation between individuals due to different intake value [31, 32], absent data of nutrient intake might also be a limitation of this study.
Another limitation of this study might be the unidentified gene polymorphisms involved in the metabolism and clearance of arsenic. Polymorphisms in a number of genes, including GSTO1 and GSTO2 from glutathione-S-transferase (GST) family which use glutathione as a reducing agent to catalyze pentavalent arsenicals to trivalent forms, GSTP1, GSTZ1, GSTM1, and GSTT1 of GSTs family which involved in the xenobiotic metabolism and play a role in the cellular response mechanism against oxidative stress induced by arsenic, arsenic 3-methyltransferase (AS3MT) which use S-adenosyl-methionine as a methyl donor to produce MMA and DMA, and methylene-tetrahydrofolate reductase (MTHFR) of one-carbon metabolism pathway, have been reported to be associated with the variation in arsenic methylation capacity [33–35] and susceptibility to arsenic-related skin lesions [36–38] and bladder cancer [39–42]. Since the role of gene polymorphisms in arsenic-related hypertension was rarely discussed which still need further research, we could not completely exclude the possible relationship between polymorphisms of these genes and susceptibility to the arsenic-related hypertension.