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DIBROMOACETIC ACID-INDUCED ELEVATIONS OF ESTRADIOL IN THE CYCLING AND OVARIECTOMOZED/ESTRADIOL-IMPLANTED FEMALE RAT
Goldman, J M. AND A S. Murr. DIBROMOACETIC ACID-INDUCED ELEVATIONS OF ESTRADIOL IN THE CYCLING AND OVARIECTOMOZED/ESTRADIOL-IMPLANTED FEMALE RAT. Presented at Society of Toxicology, Salt Lake City, UT, March 09 - 13, 2003.
Goldman, JM and Murr, AS. Dibromoacetic Acid-induced Elevations of Estradiol in Both Cycling and Ovariectomized / Estradiol-implanted Female Rats
Haloacetic acids are one of the principal classes of disinfection by-products generated by the chlorination of municipal drinking water. Two members of this class, dibromoacetic acid (DBA) and dichloroacetic acid, have been reported to affect sperm production and gonadal hormonal activity in the male rat. In females, 2 wk oral exposures have been found to disrupt estrous cyclicity, and an alteration in estradiol (E2) concentrations may underlie the effect. Using ovariectomized (OVX) Sprague-Dawley rats implanted with E2 capsules over the final 3 days of a 2 wk oral exposure to DBA (0-270 mg/kg), dose-related elevations in serum E2 were present that accompanied a reduction in the daily induced surge of luteinizing hormone seen in this type of protocol. For an evaluation of intact, regular 4-day cycles, females were again gavaged for 2 wks, this time at doses (0, 30, 60 or 120 mg/kg, in water, pH adjusted to 6.8) unlikely to impair estrous cyclicity. Over the last 4 days of dosing, daily tail nick samples of blood from each rat (1400-1500h) showed that while serum E2 on diestrus and proestrus were comparable to controls, rats in the 60 and 120 mg/kg groups had E2 levels that remained elevated on vaginal estrus instead of exhibiting the marked fall typical of 4-day cycles. Results from both intact and OVX rats also suggest the over time the extended elevations of E2 could have contributed to the disruptions in cyclicity previously noted. To explore further whether the elevation in E2 seen in the OVX/E2-implanted rats was due to an impairment in E2 metabolism, females were gavaged with DBA (0 or 270 mg/kg) for 2 wks. Over the final 3 days, they were given phenobarbital (PhB) either in the drinking water (0.1%) or by IP injection (20 mg/kg) to increase hepatic E2 metabolism. Neither PhB route caused a lowering of the DBA-induced E2 elevations although the activity of both EROD and PROD (indicators of CYP1A1 & CYP2B2 activity) was suppressed, suggesting that either a non-PhB inducible pathway (sulfation?) was being affected, or that the effect of DBA is more targeted to the estrogen-binding sites on the CYP2B1/2 and CYP1A genes and not the separate PhB-responsive unit.
(This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.)
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
REPRODUCTIVE TOXICOLOGY DIVISION