title: Evidence that atrazine and diaminochlorotriazine inhibit the estrogen/progesterone induced surge of luteinizing hormone in female Sprague-Dawley rats without changing estrogen receptor action.
abstract: High oral doses of atrazine (ATRA) disrupt normal neuroendocrine function, resulting in suppression of the luteinizing hormone (LH) surge in adult, ovariectomized (OVX) estrogen-primed female rats. While the mechanism by which ATRA inhibits LH secretion is not known, current data indicate that ATRA does have anti-estrogenic properties in vitro and in vivo. In the body, ATRA is rapidly converted to diaminochlorotriazine (DACT). The present study was conducted to investigate the effects of ATRA and DACT on the estradiol benzoate (EB)/progesterone (P) induced LH surge and to determine if such changes correlate with impaired estrogen receptor (ER) function. ATRA, administered by gavage for five consecutive days to adult OVX, female Sprague-Dawley rats, caused a dose-dependent suppression of the EB/P induced LH surge. Although to a lesser degree than ATRA, DACT significantly suppressed total plasma LH and peak LH surge levels in EB/P primed animals by 60 and 58%, respectively. DACT treatment also decreased release of LH from the pituitary in response to exogenous gonadotropin releasing hormone (GnRH) by 47% compared to control. Total plasma LH secretion was reduced by 37% compared to control, suggesting that in addition to potential hypothalamic dysfunction, pituitary function is altered. To further investigate the mechanism by which hypothalamic function might be altered, potential anti-estrogenicity of ATRA and DACT were assessed by evaluating ER function treated rats. Using an in vitro receptor binding assay, ATRA, but not DACT, inhibited binding of [(3)H]-estradiol to ER. In contrast, ATRA, administered to female rats under dosing conditions which suppressed the LH surge, neither changed the levels of unoccupied ER nor altered the estrogen induced up-regulation of progesterone receptor mRNA. Collectively, these results indicate that although ATRA is capable of binding ER in vitro, the suppression of LH after treatment with high doses of ATRA is not due to alterations of hypothalamic ER function.
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University,Fort Collins, Colorado 80523, USA.
authors.forename: Tami S
authors.initials: TS
authors.lastname: McMullin
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Alan
authors.initials: A
authors.lastname: Nagahara
authors.forename: Trent D
authors.initials: TD
authors.lastname: Lund
authors.forename: Toni
authors.initials: T
authors.lastname: Pak
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Handa
authors.forename: William H
authors.initials: WH
authors.lastname: Hanneman
mesh_terms: D000818:Animals; D007025:Anterior Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D001280:Atrazine / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood; D010052:Ovariectomy; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism; D011301:Preoptic Area; D011374:Progesterone; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D014227:Triazines; C074283:estradiol 3-benzoate; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D004958:Estradiol; D007986:Luteinizing Hormone; D001280:Atrazine