title: Induction of micronuclei in wild-type and p53(+/-) transgenic mice by inhaled bromodichloromethane.
abstract: Bromodichloromethane (BDCM) is commonly present in trace amounts in drinking water as a disinfection by-product. BDCM has been shown to be carcinogenic in mice and rats when given by gavage at relatively high doses. Genotoxic activity as well as induced regenerative cell proliferation may contribute to the carcinogenic potential of BDCM. The purpose of the current studies was to evaluate the ability of BDCM to induce micronuclei (MN) in bone marrow and blood of wild-type and p53(+/-) mice on the C57BL/6 and FVB/N genetic backgrounds using the inhalation route of exposure. Toxicity studies were being conducted in this laboratory with inhaled BDCM to select doses for longer-term cancer bioassays using wild-type and p53(+/-) transgenic mice on different genetic backgrounds. Bone marrow samples from these experiments were evaluated for the induction of MN after 1 and 3 weeks of exposure. Accumulation of MN in the peripheral blood was also evaluated at the 13-week time point of a cancer study with the p53(+/-) mice. For the 1-week time point, male C57BL/6 wild-type and p53(+/-) mice and FVB/N wild-type and p53(+/-) mice were exposed daily for 6h per day for 7 consecutive days to atmospheric BDCM concentrations of 0, 1, 10, 30, 100, or 150 ppm. In a second experiment, mice were exposed daily for 6h per day for 3 weeks to atmospheric BDCM concentrations of 0, 0.5, 1, 3, 10, or 30 ppm. Resulting levels of polychromatic erythrocytes (PCE) containing MN were assessed in the bone marrow. For all of the 1- and 3-week exposure groups, the only statistically significant increase in the percentage of bone marrow PCE cells containing MN was in the 1-week 100 ppm BDCM exposure group in the FVB/N wild-type mice (control 0.26% versus exposed 1.16%). C57BL/6 p53(+/-) mice and FVB/N p53(+/-) mice were exposed daily for 6 h per day for 13 weeks to atmospheric BDCM concentrations of 0, 0.5, 3, 10, or 15 ppm. MN were quantified in samples of peripheral blood. Statistically significant increases in the percentage of peripheral blood NCE cells containing MN were seen at the highest BDCM exposure group of 15 ppm in both the C57BL/6 p53(+/-) strain (control 0.36% versus exposed 0.67%) and the FVB/N p53(+/-) strain (control 0.36% versus exposed 0.86%). These data indicate weak induction of MN by BDCM, but only at high atmospheric concentrations relative to normal environmental exposures and with extended periods of exposure. Although comparisons are difficult because responses were negative or marginal, the p53 genotype or the genetic background did not appear to substantially alter susceptibility to the genotoxic effects of BDCM.
authors.affiliation: CIIT Centers for Health Research, Research Triangle Park, NC, USA.
authors.forename: Vincent R
authors.initials: VR
authors.lastname: Torti
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Cobb
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Wong
authors.forename: Byron E
authors.initials: BE
authors.lastname: Butterworth
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004912:Erythrocytes / Q000187:drug effects; D016158:Genes, p53 / Q000187:drug effects; D006579:Heterozygote; D019570:Inhalation Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D015162:Micronucleus Tests; D013997:Time Factors; D022882:Trihalomethanes / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D022882:Trihalomethanes; C025191:bromodichloromethane