Biotransformations of bisphenol A in a mammalian model: answers and new questions raised by low-dose metabolic fate studies in pregnant CD1 mice.
We investigated the metabolic fate of a low dose (25 micro g/kg) of bisphenol A [2,2-bis(4-hydroxy-phenyl)propane] (BPA) injected subcutaneously in CD1 pregnant mice using a tritium-labeled molecule. Analytic methods were developed to allow a radio-chromatographic profiling of BPA residues in excreta and tissues, as well as in mothers' reproductive tracts and fetuses, that contained more than 4% of the administered radioactivity. BPA was extensively metabolized by CD1 mice. Identified metabolite structures included the glucuronic acid conjugate of BPA, several double conjugates, and conjugated methoxylated compounds, demonstrating the formation of potentially reactive intermediates. Fetal radioactivity was associated with unchanged BPA, BPA glucuronide, and a disaccharide conjugate. The latter structure, as well as that of a dehydrated glucuronide conjugate of BPA (a major metabolite isolated from the digestive tract), showed that BPA metabolic routes were far more complex than previously thought. The estrogenicity of the metabolites that were identified but not tested for hormonal activity cannot be ruled out; however, in general, conjugated BPA metabolites have significantly lower potency than that of the parent compound. Thus, these data suggest the parental compound is responsible for the estrogenic effects observed in fetuses exposed to BPA during gestation in this mammalian model.
Zalko
Daniel
D
Institut National de la Recherche Agronomique, Unite Mixte de Recherche 1089 Xénobiotiques, Toulouse, France. dzalko@toulouse.inra.fr
Soto
Ana M
AM
Dolo
Laurence
L
Dorio
Céline
C
Rathahao
Estelle
E
Debrauwer
Laurent
L
Faure
Robert
R
Cravedi
Jean-Pierre
JP
D000818:Animals; D001559:Benzhydryl Compounds; D001711:Biotransformation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development; D004703:Endocrine System / Q000187:drug effects; D004968:Estrogens, Non-Steroidal / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D007279:Injections, Subcutaneous; D008431:Maternal-Fetal Exchange; D051379:Mice; D010636:Phenols / Q000008:administration & dosage / Q000378:metabolism*; D011247:Pregnancy; D012733:Sex Differentiation / Q000187:drug effects*; D014316:Tritium; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D004968:Estrogens, Non-Steroidal; D010636:Phenols; D014316:Tritium; C006780:bisphenol A; D000098826:Bisphenol A Compounds