Gl. Erexson et Kr. Tindall, Micronuclei and gene mutations in transgenic Big Blue (R) mouse and rat fibroblasts after exposure to the epoxide metabolites of 1,3-butadiene, MUT RES-GTE, 472(1-2), 2000, pp. 105-117
Citations number
49
Categorie Soggetti
Molecular Biology & Genetics
Journal title
MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS
1,3-Butadiene (BD) is a commodity compound and by-product in the manufactur
e of synthetic rubber that elicits a differential carcinogenic response in
rodents after chronic exposure. Mice are up to approximately 1000-fold more
sensitive to the tumorigenicity of inhaled ED than rats, thereby confoundi
ng human risk assessment analyses. Rodent transgenic in vivo and in vitro m
odels have been recently utilized for generating genetic toxicology data in
support of risk assessment studies. However, studies have not been extende
d to investigate multiple endpoints of genetic damage using in vitro transg
enic models. The goal of this study was to evaluate possible differences in
the production of genetic damage in transgenic Big Blue(R) mouse IBBM1) an
d rat (BBR1) fibroblasts exposed to three predominant epoxide metabolites o
f ED. Analyses of cytotoxicity, micronucleus (MN) formation, cll mutant fre
quency (MF) and apoptosis were assessed after in vitro exposure of BBM1 and
BBR1 cells exposed to various concentrations of butadiene monoepoxide (BMO
), diepoxybutane (DEB) and butadiene diolepoxide (BDE). Both BMO and DEB re
duced cell survival in BBM1 and BBR1 cells. However, BDE decreased cell sur
vival only in BBM1 cells at the concentrations evaluated. Concentration-dep
endent increases in the formation of MN was observed in both BBM1 and BBR1
cells, with DEB being the most potent followed by BDE and then BMO. The dos
e-response for mutations induced at the cll locus was essentially equal aft
er DEB exposure of BBM 1 and BBR1 fibroblasts. In contrast, the cll MF was
significantly increased only in BBM1 cells after exposure to either BMO or
BDE. These data demonstrate a differential genetic response for gene mutati
ons but not for MN formation in transgenic BBM1 and BBR1 fibroblasts and su
ggest a rodent species-specific difference in the persistence of DNA damage
that results in gene mutations. In addition, apoptosis was observed in BBR
1 cells but not in BBM1 cells when treated with any of the three ED epoxide
metabolites. This response may partially explain the differential response
to mutations induced by BMO and BDE. These data offer insight into specifi
c differences in mouse and rat cells with respect to their response to ED e
poxide metabolites. Such data may help to explain the different tumorigenic
ity results observed in rodent ED carcinogenicity studies. (C) 2000 Elsevie
r Science B.V. All rights reserved.