Dibromoacetic acid-induced elevations in circulating estradiol: effects in both cycling and ovariectomized/steroid-primed female rats.
Oral exposures to high concentrations of the drinking water disinfection by-product dibromoacetic acid (DBA) over the course of 14 days have been found to disrupt estrous cyclicity in the female rat. In order to investigate possible alterations in the relevant hormonal regulatory mechanisms, female Sprague-Dawley rats were gavaged for 2 weeks with 270 mg/kg DBA, ovariectomized (OVX) and implanted with estradiol capsules. For these females, the induced luteinizing hormone (LH) surge in these animals showed a borderline suppression in peak LH concentrations that was accompanied by a marked increase in circulating estradiol. This elevation in estradiol was DBA dose-related and, for intact, normally cycling females receiving lower doses of DBA (60 and 120 mg/kg, 14 days), was present on the day of estrus, at a time when a dramatic fall from proestrous concentrations is normally evident. Evaluations of liver microsomal cytochrome p450 activity in OVX/estradiol-implanted rats showed a suppression in ethoxyresorufin-O-deethylase (EROD) and pentoxyresorufin-O-deethylase (PROD) activity (indications of the activity of CYP1A and 2B, respectively-two key enzymes in estradiol oxidative metabolism). Phenobarbital (PhB) exposure in these animals did show induction of this activity, but was unable to lower E2 concentrations. This suggests that a DBA-induced suppression in estradiol catabolism is present and may either involve a targeted effect on the estrogen binding site on the CYP2B1/2 and CYP1A genes apart from the PhB-responsive unit, or a second pathway (possibly sulfation) that is not PhB-inducible.
Goldman
Jerome M
JM
Endocrinology Branch, Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA. goldman.jerome@epa.gov
Murr
Ashley S
AS
D000085:Acetates / Q000008:administration & dosage / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects; D019362:Cytochrome P-450 CYP2B1 / Q000187:drug effects; D004202:Disinfectants / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000097:blood; D004971:Estrus / Q000187:drug effects* / Q000502:physiology; D005260:Female; D007986:Luteinizing Hormone / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology; D010052:Ovariectomy; D000091402:Prohibitins; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000085:Acetates; D004202:Disinfectants; C000717332:Phb protein, rat; D000091402:Prohibitins; D004958:Estradiol; C088674:dibromoacetic acid; D007986:Luteinizing Hormone; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1