Effects of atrazine on the HPG and HPA axes and steroidogenic pathways in females: relevance to reproductive function and breast, ovarian and uterine cancer

We reviewed the mode of action (MOA) underlying the effect of the chlorotriazines on female reproduction and mammary tumor development in rats. Age-associated changes in the HPO hormonal environment of the female drive the development of mammary gland tumors in several rat strains. The adverse outcome pathway for tumor development involves a disruption of the ovulatory surge of luteinizing hormone (LH) caused by changes in the hypothalamic control of LH release. The ensuing persistence of unruptured ovarian follicles produces elevated blood estradiol (E2) and prolactin, both known to induce mammary gland tumors. High doses of atrazine induce premature reproductive aging and elevated E2, which is commonly found later in aging female rats. The change in HPO in aging rodents is distinctly different from that seen in aging women. In humans, reproductive aging (menopause) is driven by the loss of ovarian follicles and ensuing low serum E2. Alternate MoAs were examined, including the effect of atrazine on estrogen synthesis, atrazine's potential to bind to estrogen receptors, Erα, Erβ, or G-protein coupled, estrogen receptors (GPER) <i>in vitro</i>. The chlorotriazines do not bind to ER receptors; high doses may have anti-E2 effects. MOAs hypothesized from <i>in vitro</i> studies were of limited utility in predicting <i>in vivo</i> effects of atrazine because of the effects of metabolism and the kinetics of elimination <i>in vivo</i>. A review of the epidemiology literature indicated there is no consistent evidence of a causal association between chlorotriazine exposure and the incidence of breast, ovarian, or uterine cancers in women.