Urinary metabolic biomarkers link induced oxidative stress from general arsenic exposure to male infertility in a Han Chinese Population

Although animal studies have identified that high exposure levels of the more toxic arsenite (AsiIII) can induce adverse effects on male semen quality, there is a lack of corresponding human exposure and epidemiological studies to support the hypothesis that general environmental arsenic exposure can impair male fertility. To address this, we designed a case-control study investigating possible correlations between the concentrations of different arsenic species in urine, urinary metabolic biomarkers, and infertility characterized by poor semen quality. Arsenate (AsiV) was associated with infertility in a concentration-dependent manner: in comparison with the 1st quartile, subjects with AsiV levels above the median were more likely to exhibit male idiopathic infertility with a 4.9-fold [95% confidence interval (CI), 1.8-13.6] and 13.6-fold [95% CI, 4.8-38.6] increase in risk for the 3rd and 4th quartiles, respectively. Dimethylarsinic acid (DMAV) and arsenobetaine (AsBV) levels were significantly higher among infertility cases compared to controls in the absence of any dosage trend. We also observed some biomarkers, which indicate abnormalities in testicular function and Leydig cell steroidogenesis (including impaired sperm metabolism and maturation, or anti-oxidation during spermatogenesis), were dose-dependently correlated with both male infertility and AsiV concentrations; the latter correlation was independent of disease. These included acylcarnitines, aspartic acid and hydroxyestrone, which were negatively associated with infertility; and, uridine and methylxanthine, which were positively associated. In conclusion, for the first time we show that elevated urinary concentrations of AsiV from general exposure are strongly associated with male infertility, and arsenic species may exert toxicity via oxidative stress and sexual hormone disrupting mechanisms as shown by related biomarkers.