Bisphenol A

BPA is a diphenolic compound with a chemical structure similar to that of DES (Fig. 1) but a much lower estrogenicity. It is widely used, e.g., for the production of polycarbonates and epoxy resins, and produced in large amounts. Some of the materials are used for containing food and potable water and provide a source for human exposure, since BPA has been reported to leach from such containers.

Conventional short-term assays have shown no evidence for genotoxicity (as summarized by Tsutsui et al. [68], and a carcinogenicity bioassay in male and female Fischer 344 rats and B6C3F1 mice was negative with the exception of a marginally significant increase in leukemia in male rats only [69].

More recently, the potential of BPA to form DNA adducts and to induce aneuploidy has been studied. BPA was chemically (with potassium nitrosodisul-fonate) and enzymatically (with peroxidase/hydrogen peroxide) oxidized to a catechol and subsequently to the respective ortho-quinone (Fig. 8), which gave rise to several DNA adducts under cell-free conditions [70]. After oral or intraperitoneal administration of a very high dose (200 mg/kg body weight) of BPA to male CD-1 rats, two major and several minor DNA adducts were detected in the liver at a level of about 10 total adducts per 109 nucleotides using the 32P-postlabeling technique [71]. The major in vivo liver DNA adducts of BPA matched two of four products of the cell-free reaction of BPA-quinone with DNA in thin layer chromatography. This led the authors to conclude that the quinone of a BPA-catechol is the DNA-binding metabolite (Fig. 8). However, the exact chemical structures of the adducts have not yet been reported, nor has the unequivocal formation of BPA catechol in vivo. An in vitro study with hepatic

O BPA quinone

Fig. 8. Proposed metabolic activation and genotoxic effects of BPA

O BPA quinone

Fig. 8. Proposed metabolic activation and genotoxic effects of BPA

microsomes from aroclor-induced male rats showed a very poor oxidative metabolism of BPA with the formation of only trace amounts of BPA catechol, and no type I binding spectrum to cytochrome P450 with BPA concentration up to 20 nM; higher concentrations caused denaturation of microsomal proteins [72]. Recent reports have studied the inhibitory effects of BPA on various hepatic cytochrome P450 activities of rats [73] and humans [74] in detail. A recent study on the metabolism of 14C-labeled BPA in Fischer 344 rats showed that orally administered BPA is rapidly glucuronidated [75]. These data imply that BPA, in contrast to other phenolic compounds discussed above, like E2, EN, GEN, and DES, is a poor substrate for catechol formation. This fact and the rapid glu-curonidation of BPA render it unlikely that significant DNA adduction will occur at low levels of exposure.

Because of the structural similarity of BPA to DES, the potential of BPA to interfere with microtubules (MT) and to induce aneuploidy has been studied. Indeed, BPA inhibited cell-free MT assembly and induced mitotic arrest and micronuclei containing whole chromosomes in cultured V79 cells in a DES-like manner, although with a lower activity [76,77]. Treatment of SHE cells with BPA

induced morphological transformation and near-diploid aneuploidy but failed to induce gene mutations [78], also behaving like DES in this respect (see Sect. 3.1). When four other bisphenols structurally related to BPA were studied, a good correlation of cell-free MT inhibition and micronucleus induction in V79 cells [76] with aneuploidy induction and cell transformation in SHE cells was observed [68]. As discussed above for DES, aneuploidy induction may also play an important role in the genotoxicity of BPA and other bisphenols.

Was this article helpful?

0 0

Post a comment