Genetic Alterations in Brain Tumors Following 1,3-Butadiene Exposure in B6C3F1 Mice

Abstract

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 → 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.

Human Exposure to Selected Animal Neurocarcinogens: A Biomarker-Based Assessment and Implications for Brain Tumor Epidemiology

“…Occupational studies in the rubber industry found increased incidence of leukemia (Delzell et al , 2006) and lymphosarcoma (Divine and Hartman, 2001). A variety of tumors, including brain tumors, are found in animal models exposed to 1,3-butadiene (Kim et al , 2005), which supports both its carcinogenicity and potential for being a neurocarcinogen. Mice exposed to high (625-ppm) levels of 1,3-butadiene for at least 13 weeks have an increased risk of malignant glioma (NTP,.1993).…”

A Review of the Molecular Mechanisms of Chemically Induced Neoplasia in Rat and Mouse Models in National Toxicology Program Bioassays and Their Relevance to Human Cancer

“…Along with the increased incidence of lung tumors, harder-ian gland tumors, hemangiosarcomas, and lymphomas, exposure to 1,3-butadiene surprisingly resulted in an increased incidence of brain tumors in B6C3F1 mice (Kim et al 2005). While the central nervous system is a rare target for carcinogenesis in NTP bioassays (Ton et al 2007), there was an increase in glioma and neuroblastoma formation with locational and morphologic similarities to their human counterparts (Kleihues et al 2002).…”

“…Hepatocellular carcinoma (HCC) accounts for more than 90% of primary hepatic neoplasia (Kim, Sills, and Houle 2005). The pathogenesis of this disease in humans is multifactorial, associated with various infectious agents, carcinogens, and environmental and lifestyle factors (Coleman 2003).…”

“…The pathogenesis of this disease in humans is multifactorial, associated with various infectious agents, carcinogens, and environmental and lifestyle factors (Coleman 2003). In B6C3F1 mice, hepatocellular adenoma (HCA) is the most common spontaneous liver neoplasm second to HCC and occurs more commonly in males than in females (Kim, Sills, and Houle 2005). Hepatoblastoma (HB) is a malignant embryonal tumor affecting predominantly children under 3 years of age (Koch et al 1999).…”

“…Hepatoblastoma (HB) is a malignant embryonal tumor affecting predominantly children under 3 years of age (Koch et al 1999). It not only is the most common malignant hepatic tumor in children, accounting for 1.5 cases per 1 million, occurring most often sporadically, but also is associated with familial syndromes such as familial adenomatous polyposis coli (FAP) or Beckwith-Wiedemann syndrome (Ishak and Glunz 1967; Kim, Sills, and Houle 2005; Steenman, Westerveld, and Mannens 2000). Hepatoblastomas in mice rarely occur spontaneously, while higher incidences may occur in chemically induced models and may occur within a preexisting HCC or HCA (Turusov et al 2002).…”