Mutagenicity of bisphenol A (4,4′‐isopropylidenediphenol) in vitro: effects of nitrosylation

Abstract

Bisphenol A (4,4'-isopropylidenediphenol) is a common component of polycarbonate plastics and epoxy resins. Since bisphenol A-containing plastics and resins have found uses in food-contact items, its potential migration into foodstuffs and possible health consequences have been the focus of many recent studies. However, the potential mutagenic activation of bisphenol A by nitrosylation has received little attention. Incubation of bisphenol A with sodium nitrite under acidic conditions produced a yellow-brown product. When nitrosylated bisphenol A was tested in the Ames Salmonella/microsome assay at 100 ng to 1 mg/plate, dose-dependent increases in mutagenicity were found in both TA98 and TA100 Salmonella strains. These results indicated the presence of a direct-acting mutagenic activity causing both frameshift and base pair mutations, respectively. When compared to colony formation in untreated controls, the addition of rat liver S9 for metabolic activation had little influence on revertant colony formation. Unreacted bisphenol A dissolved in DMSO, acidic buffer, or inactivated nitrosylation solution showed negligible mutagenicity. When the nature of the mutagenic changes was examined using the Ames II trade mark Assay, a variety of base pair changes was found including T:A to A:T - S9, G:C to A:T +/- S9,C:G to A:T +/- S9 and C:G to G:C +/- S9. Bisphenol A also induced frameshift mutations at G:C sites. In addition, the presence of electrophiles was shown by the production of an intensely coloured orange-red product upon incubation of nitrosylated bisphenol A with the nucleophile 4-(4'-nitrobenzyl)pyridine. These findings suggest that migration of bisphenol A into nitrite containing foodstuffs, or its ingestion in the presence of nitrite, could lead to the formation of mutagenic compounds.

An evaluation of evidence for the carcinogenic activity of bisphenol A

“…Thus, consideration of BPA as a carcinogen warrants assessment of its genotoxic capabilities. Admittedly, most studies evaluating BPA-induced genetic alterations have involved in vitro assays, many of which have reported a lack of mutagenic activity [66][67][68]. However, some in vitro assays have reported genotoxic activity that correlates with morphological transformation [69] or aneuploidy in oocytes [70] and in vivo analyses have also indicated that BPA can induce aneuploidy in germ cells following embryonic exposure of C57BL/6 female mice to BPA via the maternal circulation beginning on 11.5 dpc [26;71].…”

Changes in the Mutagenic and Estrogenic Activities of 17β-Estradiol after Treatment with Nitrite

“…10) Schrader et al have confirmed that the mutagenicity of bisphenol A was expressed by nitrosylation. 11) We have also demonstrated that bisphenol A showed mutagenic activity after a nitrite treatment under acidic conditions. 12) Thus, 17-estradiol might show mutagenicity after the reaction with nitrite under acidic conditions.…”

“…G:C, in addition to the generation of G:C frame-shift mutations. 11) We have previously demonstrated by using electron spin resonance (ESR) that the reaction mixture of BPA and nitrite, which showed mutagenic activity, generated radicals. 12) We therefore examined by ESR the radicals formed from the reaction mixture of nitrite and 17-estradiol.…”

Focus on Bisphenol A, an Uncertain Environmental Pollutant

“…The native BPA is non-mutagenic, however the incubation of BPA with sodium nitrite in an acidic environment activates the BPA into a direct-acting frameshift type and base pair mutagen in a variety of sites of nucleic acid in the Ames Salmonella assay (Schrader et al, 2002).…”