Detection and characterization of mechanisms of action of aneugenic chemicals

Abstract

A comprehensive evaluation of the genotoxic potential of chemicals requires the assessment of the ability to induce gene mutations and structural chromosome (clastogenic activity) and numerical chromosome (aneugenic activity) aberrations. Aneuploidy is a major cause of human reproductive failure and an important contributor to cancer and it is therefore important that any increase in its frequency due to chemical exposures should be recognized and controlled. The in vitro binucleate cell micronucleus assay provides a powerful tool to determine the ability of a chemical to induce chromosome damage. The application of an anti-kinetochore antibody to micronuclei allows their classification into kinetochore-positive and kinetochorenegative, indicating their origin by aneugenic or clastogenic mechanisms, respectively. The availability of chromosomespecific centromere probes allows the analysis of the segregation of chromosomes into the daughter nuclei of binucleate cells to evaluate chromosome non-disjunction. Quantitative relationships between the two major causes of aneuploidy, chromosome loss and non-disjunction, can be determined. The mechanisms leading to chromosome loss and non-disjunction can be investigated by the analysis of morphological and structural changes in the cell division apparatus by the application of specific stains and antibodies for various cell division components. We illustrate such analyses by the demonstration of the interaction of the monomer bisphenol-A with the centrosome of the mitotic spindle and the folic acid antagonist pyrimethamine with the centromeres of chromosomes. Both types of modifications lead to the induction of aneuploidy in exposed cells. Our studies also implicate the products of the p53 and XPD genes in the regulation of the fidelity of chromosome segregation at mitosis.

Clastogenic effects of bisphenol A on human cultured lymphocytes

“…Similarly, Xin et al 22 observed a significant increase of MNs frequency in CHO cells after 24 h exposure to doses of 80 and 120 µM of BP-A (corresponding to 0.018 and 0.027 µg/mL, respectively). Finally, Parry et al 20 and Johnson and Parry 36 showed that BP-A cause MNs induction, also in these cases in a dosedependent manner, on MCL5 and AHH-1 human lymphoblastoid cell lines and Chinese hamster V79 cells.…”

The adverse effects of bisphenol A on male albino rats

“…One of the possibilities of the existence of micronuclei could be due to the aneugenic effects of BPA (Hunt et al, 2003;Quick, Parry, & Parry, 2008). Also, BPA was evaluated for its ability to induce MN in cell types such as the human lymphoblastoid cell line MCL5 (Parry et al, 2002), human lymphoblastoid cell line AHH-1, and Chinese hamster V79 cells (Johnson & Parry, 2008). In each case, BPA caused chromosome separation anomalies of non-disjunction and MN, in a dosedependent manner.…”

“…The genetic toxicity of BPA in somatic cells has been reported in vitro using micronucleus test in hamster V79 cells (Pfeiffer, Rosenberg, Deuschel, & Metzler, 1997), human MCL-5 cells (Parry et al, 2002), human lymphoblastoid cell lines, and Chinese hamster V79 cell lines (Johnson & Parry, 2008).…”

Bisphenol A: Understanding Its Health Effects from the Studies Performed on Model Organisms

“…This inding suggests that exposure to BPA during the time that meiosis resumes in the mid-cycle surge by luteinizing hormone (LH) can result in an increase in foetal aneuploidy and subsequent spontaneous abortion in humans [47]. The efect of BPA on aneuploidy has also been examined in cell culture [48][49][50][51]. In the study by Tsutsui et al [48,49] embryo cells with BPA (100 μM) for 48 hours resulted in statistically signiicant increases in the percentage of aneuploid metaphases with chromosome losses.…”

“…BPA enters the living system inconspicuously through various routes, particularly through food and water contamination, and creates multitude of imperilments at cellular, molecular and genetic level. The EC 50 and LC 50 values of BPA range from 1.0 to 10 mg/L (Environment Canada 2008), and BPA is declared as 'moderately toxic' and 'toxic' to aquatic biota by the European Commission and the United States Environmental Protection Agency (US EPA), respectively [4], Commission of the European Communities 1996]. Moreover, environmentally relevant concentrations (12 mg/L or lower) of BPA were also found to be harmful as far as wildlife is concerned [5].…”