Characterization of a new biotransformation pathway of bisphenol A and quantitation of DNA lesions in HL-60 and MCF-7 cells

Abstract

Bisphenol A (BPA) is largely used for plastic production and widely distributed in the environment, which favors chronic human exposure to this xenobiotic since the intrauterine stage. There is great concern about increased risk of development of different types of cancer by BPA exposure, being that four modes of BPA action are considered to contribute to this increase: endocrine estrogenic disruption, induction of tumor progression, genotoxicity, and development reprogramming with increased susceptibility to other carcinogenic events. In vitro and in vivo studies have revealed these modes of action, but studies are currently necessary to understand the underlying mechanisms to the observed effects.As BPA induces damage to the bone marrow and cancer to the hematopoietic system of rodents, one objective here is to investigate DNA alterations in HL-60 cells due to BPA biotransformation by myeloperoxidase (MPO). Such biotransformation pathway has not been investigated yet. The influence of BPA biotransformation by cytochrome P450 and of its binding to estrogen receptors for induction of DNA alterations will be also evaluated in MCF-7 cells. For this purpose, a set of DNA adducts induced by BPA will be obtained to serve as standards for quantitation in DNA of the exposed cells. Lesions due to oxidative damage, resulting from ROS or a,b-unsaturated aldehyde binding to DNA, will be also quantitated in cell DNA, as well as the global DNA methylation. Such approach will allow to define the importance of some DNA adducts as markers for biological damage monitoring induced by BPA in vivo, beyond the knowledge of the underlying mechanisms for DNA lesion induction. (AU)