Review of the effect of atrazine on the HPG axes and steroidogenic pathways in males: relevance for testicular and prostate cancer

Subacute, subchronic, and chronic rodent studies on atrazine were evaluated to determine the no observed adverse effect levels (NOAEL) for male reproductive toxicity and carcinogenicity. <i>In vitro</i> studies were also evaluated for the effect of atrazine on molecular pathways related to male reproductive function and potential mechanisms for cancer. Gestational exposure to high doses of atrazine delayed male development post-partum. The NOAEL in male offspring following perinatal exposure of the dam from PND 1-4 was ≥ 25 mg/kg/day. The NOAEL for an increase in prostate inflammation on PND 120 was 12.5 mg/kg/day. Exposure of peripubertal males to atrazine reduced serum and intratesticular testosterone levels, decreased gonadal and prostate gland weights, and decreased sperm count and motility. The NOAELs were approximately 25 mg/kg. Increased plasma estrone and estradiol levels at atrazine doses of 50-200 mg/kg/day were associated with elevated aromatase expression and impaired fluid absorption in the efferent ductules of the testes. Oxidative stress, detected <i>in vivo</i> and <i>in vitro</i> at high atrazine doses, was associated with reduced testosterone levels, increased cytokine activity, and inflammation. The NOAEL for these effects was 25 mg/kg/day. Lifetime doses up to 25 mg/kg/day of atrazine did not result in an elevated incidence of prostate or testicular cancer in rodents. An increased incidence of interstitial cell tumors in male rats (53 mg/kg/day) was not significant after adjusting for the increased survival. Finally, epidemiological studies did not provide any consistent evidence of a causal association between atrazine exposure and testicular or prostate cancer in men.