| Sign In to gain access to subscriptions and/or personal tools. |
Genetic Alterations in Brain Tumors Following 1,3-Butadiene Exposure in B6C3F1 Mice
1 Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA Correspondence: Address correspondence to: Dr. Robert C. Sills, National Institute of Environmental Health Sciences, MD B3-08, 111 Alexander Drive, Research Triangle Park, NC 27709, USA; e-mail:sills{at}niehs.nih.gov
The nervous system of the B6C3F1 mouse has rarely been a target for chemical carcinogenesis in the National Toxicology Program (NTP) bioassays. However, 6 malignant gliomas and 2 neuroblastomas were observed in B6C3F1 mice exposed to 625 ppm 1,3-butadiene (NTP technical reports 288 and 434). These mouse brain tumors were evaluated with regard to the profile of genetic alterations that are observed in human brain tumors. Alterations in the p53 tumor suppressor gene were common. Missense mutations were observed in 3/6 malignant gliomas and 2/2 neuroblastomas and were associated with loss of heterozygosity. Most of the mutations occurred in exons 5–8 of the p53 gene and were G
Key Words: B6C3F1 mouse • 1,3-butadiene • brain tumors • p53 • Ink4a/Arf • mutation • loss of heterozygosity • neurocarcinogenesis Abbreviations: DNA, Deoxyribonucleic acid • dNTP, Deoxynucleotide • EGFR, Epidermal growth factor receptor • LOH, Loss of heterozygosity • NTP, National Toxicology Program • PBS, Phosphate buffered saline • PCR, Polymerase chain reaction • PTEN, Phosphatase and tensin homologue
Toxicologic Pathology, Vol. 33, No. 3,
307-312 (2005) |
|
|||
 |
|
|
 |
|
Sign In to gain access to subscriptions and/or personal tools.
A transitions, and did not involve CpG sites. Loss of heterozygosity at the Ink4a/Arf gene locus was observed in 5/5 malignant gliomas and 1/1 neuroblastoma, while the PTEN (phosphatase and tensin homologue) gene locus was unaffected by deletions. One of 2 neuroblastomas had a mutation in codon 61 of H-ras, while H-ras mutations were not observed in the malignant gliomas examined. Only 1 brain tumor has been reported from control mice of over 500 NTP studies. This malignant glioma showed no evidence of alterations in the p53 gene or K - and H-ras mutations. It is likely that the specific genetic alterations observed were induced or selected for by 1,3-butadiene treatment that contributed to the development of mouse brain tumors. The observed findings are similar in part to the genetic alterations reported in human brain tumors.