Chloro‐s‐triazine antagonism of estrogen action: Limited interaction with estrogen receptor binding

Abstract

In an accompanying article (see pp. 183-196), it was reported that administration of very high doses of the chlorotriazine herbicides atrazine, simazine, and diaminochlorotriazine (DACT), a common metabolite, expressed antiestrogenic activity in uteri of female Sprague-Dawley rats without expressing intrinsic estrogenic activity. In the present article, studies of chlorotriazine interaction with rat uterine estrogen receptors (ER) are reported. Under equilibrium conditions, none of the triazine compounds showed an ability to compete against binding of radiolabeled estradiol to ER. A weak competition was evident only if cytosols were preincubated with triazines at 25 degrees C prior to introduction of tracer. Competition was very weak, with kl estimates of 10-100 microM. A limited Scatchard analysis suggested a competitive type of inhibition. Sucrose gradient analysis of cytosol incubations showed that triazine interaction with the 4S isoform of ER may be greater than with the 8S form. When administered to ovariectomized rats for 2 d at 300 mg/kg/d, atrazine, simazine, or DACT all reduced uterine ER binding capacity by approximately 30%. Results from the receptor binding studies indicated that triazine competition against ER binding occurred to a much lesser degree than inhibition of estrogen-mediated responses reported in accompanying articles. This suggests that the complete responses to triazines may include inhibition of events other than or in addition to ER binding of estrogen.

Possible enhancing effects of atrazine and nonylphenol on 7,12‐dimethylbenz[a]anthracene‐induced mammary tumor development in human c‐Ha‐ras proto‐oncogene transgenic rats

“…[41][42][43] As evidenced by our observations in MCF-7 assay, it does not bind to the estrogen receptor. The estrogenic effects associated with the triazine herbicides are not estrogen receptor-mediated, but may be explained partly by the ability of the compounds to induce aromatase.…”

Collaborative work on evaluation of ovarian toxicity 14) Two- or four-week repeated-dose studies and fertility study of atrazine in female rats

“…The increased numbers of large-sized atretic follicles observed in this study may have been induced by lower LH secretion caused by atrazine treatment and subsequently affected by inhibition of ovulation. The uterine atrophy observed in the 300 mg/kg group may be attributable to inhibition of the binding of estrogen to its receptor by atrazine (Tennant et al, 1994;McMullin et al, 2004) and to a reduction in estrogen levels due to the increased numbers of atretic follicles resulting from atrazine treatment.…”

“…As part of the collaborative study on toxicity related to female fertility, we performed experiments using atrazine, which is used as a herbicide in agriculture, and known to induce endocrine imbalances in female rats, such as suppression of the secretion of luteinizing hormone (LH) in ovariectomized rats (Cooper et al, 2000;McMullin et al, 2004), inhibition of the binding of estrogen to its receptor (Tennant et al, 1994;McMullin et al, 2004), and elevation of serum progesterone levels (Cooper et al, 1996). Atrazine also induces disruption of the estrous cycle characterized by the absence of recent corpora lutea and well developed follicles in the ovary (Cooper et al, 1996).…”

Atrazine-induced hermaphroditism at 0.1 ppb in American leopard frogs (Rana pipiens): laboratory and field evidence.

“…Furthermore, atrazine exposure resulted in testicular oogenesis and even induced growth (vitellogenesis) of the oocytes in slower developing males, but had no effect in females. Atrazine does not bind the estrogen receptor (Tennant et al 1994), but studies in reptiles (Crain et al 1997), mammals (Sanderson et al 2000(Sanderson et al , 2001, and fish (Sanderson et al 2001) showed that atrazine induces aromatase and thereby increases the production of endogenous estrogen. The demasculinization (failure to induce spermatogenesis) and feminization (induction and growth of oocytes) observed in the current study and previous work Tevera-Mendoza et al 2002) are explainable via the proposed mechanism.…”