Biotransformations of bisphenol A in a mammalian model: answers and new questions raised by low-dose metabolic fate studies in pregnant CD1 mice.

Abstract

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.

Impact of oral bisphenol A at reference doses on intestinal barrier function and sex differences after perinatal exposure in rats

“…A high-permeability state in early infancy reflects the development of the gut mucosal barrier (38) that precedes a period of epithelial TJ sealing to provide an effective barrier against foreign agents (19,20). BPA ingested by mothers is present in fetal tissues (39) and human milk (40), and leakage of BPA from polycarbonate baby bottles under real use conditions has been demonstrated (6). As ERβ is the only ER detectable in human fetal colon (41), we speculated that a BPA-mediated alteration of gut permeability in the perinatal period of life may have restricting effects on the developing immune system in the colon.…”

NTP‐CERHR expert panel report on the reproductive and developmental toxicity of bisphenol A

“…In pups from the 10 mg/L group, the highest concentration of bisphenol A was detected in kidney (B24 mg/kg wet weight), followed by testis (B20 mg/kg wet weight), brain (B18 mg/kg wet weight), and liver (B11 mg/kg wet weight). Zalko et al (2003) examined metabolism and distribution of bisphenol A in pregnant CD-1 mice. A series of studies was conducted in which mice were treated with 3 H-bisphenol A (499.9% purity)/unlabeled bisphenol A (499% purity).…”

Effects of estrogens on proliferation and differentiation of neural stem/progenitor cells

“…1A); whereas when EGF was added instead of FGF-2 as a mitogen, the number or size of neurospheres was rather smaller even after daily addition of the growth factor (data not shown). After 7 days, the cells were mechanically dissociated from the spheres in Hank's balanced salts modified solution representative estrogen-like endocrine-disrupting chemical, has the ability to bind to estrogen receptors (24); that BPA is capable of penetrating the blood-brain barrier (15); and that the maternal exposure to BPA results in its higher concentrations in the mouse fetus and amniotic fluid than in the maternal blood (23). These results indicate the possibility that BPA may affect fetal brain development.…”