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Atrazine-induced elevation or attenuation of the LH surge in the ovariectomized, estrogen-primed female rat: role of adrenal progesterone
Goldman, J., L. Davis, A. Murr, AND R. Cooper. Atrazine-induced elevation or attenuation of the LH surge in the ovariectomized, estrogen-primed female rat: role of adrenal progesterone. REPRODUCTION. BioScientifica Ltd., Bristol, Uk, 146(4):305-14, (2013).
Multiple daily exposures to the herbicide atrazine have been reported to suppress the surge of luteinizing hormone (LH) in both cycling female rats and those that are ovariectomized (OVX) and exogenously primed with steroids. Additional studies have also found elevations in both estradiol (E2) and progesterone (P4), hormones that serve complementary functions in generating the LH surge, depending on the temporal relationships ofeach to the appearance of the surge. The effects of atrazine dose and exposure duration on P4 temporal dynamics were examined using OVX, E2-primed rats. When administered at 1300h, a single oral dose of 100 mg/kg, previously shown to suppress the surge after multiple treatments, significantly enhanced the afternoon LH surge. In contrast, 4 consecutive daily treatments caused a significant suppression, whereas no effects were present following 2 days of dosing. Prompt elevations in serum P4 concentrations, likely attributable to adrenal secretion, were present for the 1 and 4 day exposures. At 30 minutes after dosing, both treatments showed a marked, rapid rise followed at 1 hour by a precipitous fall. A dose-response assessment was subsequently conducted with 0, 10, 30 and 100 mg/kg atrazine for 1 and 4 days. At 1 day, 100 mg/kg caused similar elevations in circulating P4, the LH peak and AUC, whereas 4 daily exposures resulted in a shift to a reduced AUC. This influence on the LH surge from elevations in adrenal P4 secretion suggests that the effectiveness of atrazine in inducing bidirectional shifts in LH depends on both the dosage administered and importantly on the temporal association of exposure to the appearance ofthe surge.
The herbicide atrazine is one of the most heavily used pesticides in the U.S. and has been the subject of multiple EPA Scientific Advisory Panel meetings. Its adverse outcome pathway in mammals is still poorly defined. The present research has implicated an atrazine-induced elevation in circulating concentrations of the sex steroid progesterone as a major contributing factor to alterations of the ovulatory luteinizing hormone (LH) surge in female rodents. The effect is bidirectional in that a single oral exposure given just prior to an anticipated LH surge will enhance the rise in LH, whereas multiple exposures will cause a suppression. Using an ovariectomized, estradiol-primed rodent model, atrazine was found to trigger a large increase in adrenal progesterone within minutes of exposures and the difference in the direction of the effect on the surge is consistent with what is known about the temporal influence of progesterone on LH in both humans and rodents. The data presented in this manuscript will provide important information to the Program Offices that addresses an adverse outcome pathway that both implicates the adrenals and shows a marked directional distinction between single acute and more extended exposures.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
TOXICOLOGY ASSESSMENT DIVISION
ENDOCRINE TOXICOLOGY BRANCH