Point mutations of K-ras and H-ras genes in forestomach neoplasms from control B6C3F1 mice and following exposure to 1,3-butadiene, isoprene or chloroprene for up to 2-years

1,3 Butadiene (BD), isoprene (IP) and chloroprene (CP) are structural analo gs. There were significantly increased incidences of forestomach neoplasms in J36C3F1 mice exposed to BD, IP or CP by inhalation for up to 2-years. Th e present study was designed to characterize genetic alterations in K- and H-ras proto-oncogenes in a total of 52 spontaneous and chemically induced f orestomach neoplasms. ras mutations were identified by restriction fragment length polymorphism, single strand conformational polymorphism analysis, a nd cycle sequencing of PCR-amplified DNA isolated from paraffin-embedded fo restomach neoplasms. A higher frequency of K- and H-ras mutations was ident ified in BD-, IP- and CP-induced forestomach neoplasms (83, 70 and 57%, res pectively, or combined 31/41, 76%) when compared to spontaneous forestomach neoplasms (4/11. 36%). Also a high frequency of H-ras codon 61 CAA --> CTA transversions (10/41, 24%) was detected in chemically induced forestomach neoplasms, but none were present in the spontaneous forestomach neoplasms e xamined. Furthermore, an increased frequency (treated 13/41, 32% versus unt reated 1/11, 9%) of GGC --> CGC transversion at K-ras codon 13 was seen in BD-, and IP-induced forestomach neoplasms, similar to the predominant K-ras mutation pattern observed in BD-induced mouse lung neoplasms. These data s uggest that the epoxide intermediates of the structurally related chemicals (BD, IP, and CP) may cause DNA damage in K-ras and H-ras proto-oncogenes o f B6C3F1 mice following inhalation exposure and that mutational activation of these genes may be critical events in the pathogenesis of forestomach ne oplasms induced in the B6C3F1 mouse. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.