Differential mutagenicity of aflatoxin B₁ in the liver of neonatal and adult mice

Abstract

Children are generally more sensitive to toxicants than adults, including an increased sensitivity to genotoxic carcinogens. We previously demonstrated that neonatal mice are also more sensitive to the mutagenic effects of the direct alkylating agents N-ethyl-N-nitrosoamine and the arylamine 4-aminobiphenyl than adult mice. In this study, we have evaluated the effect of age on the mutagenicity of the fungal toxin and liver carcinogen aflatoxin B(1) (AFB(1)). Neonatal Big Blue transgenic mice were treated with 6 mg/kg AFB(1), a treatment that produces liver tumors, while adult mice were treated with 6 and 60 mg/kg AFB(1), treatments that do not result in tumors. The cII liver mutant frequency (MF) in mice treated with AFB(1) as neonates was 22-fold higher than in control neonatal mice, whereas the treatment of adult mice with either dose of AFB(1) did not significantly increase the liver MF over the controls. In AFB(1)-treated neonatal mice, the frequency of G:C --> T:A transversion, a major type of mutation induced by AFB(1), was about 82-fold higher than for the control and 31-fold higher than for adult mice treated with 60 mg/kg AFB(1). Our mutagenicity findings parallel the relative carcinogenicity of AFB(1) in neonatal and adult mice, and are consistent with previous observations of the lower level of hepatic glutathione S-transferase and higher level of hepatic AFB(1)-DNA adduction in neonatal mice compared to adult mice.

A Single Neonatal Exposure to Aflatoxin B1 Induces Prolonged Genetic Damage in Two Loci of Mouse Liver

“…Earlier analyses showed a 13-to 15-fold increase in the MF of the gpt transgene at 3 weeks after treatment of 4-day-old mice (Woo et al, 2011); our present findings show that the MF continued to increase up to 20-fold over DMSO-treated controls at 10 weeks thereafter. These results are in agreement with another study that found a 22-fold increase in base substitution and frameshift mutations in the cII transgene of neonatal Big Blue B6C3F1 mice 6 weeks after treatment with AFB 1 (Chen et al, 2010). The slower increase in MF in the liver from 3 to 10 weeks was very likely due to the decrease in growth rate of the liver after 3 weeks.…”

“…a Because few mutants were available for analysis, data from male and female mice were combined. bacterial reporter genes in transgenic mice established that neonatal exposure to AFB 1 leads to a 20-fold increase in the frequency of point mutations in the gpt gene in the liver (Chen et al, 2010;Woo et al, 2011). In the present investigation, we studied the ability of AFB 1 to induce mutations in the gam and red genes of a λEG10 reporter in mouse liver.…”

“…Mutations produced by genotoxicants are essential for initiation of the carcinogenic process by most chemical carcinogens. Several studies have characterized the number and types of mutations produced in animal models shortly after treatment with AFB 1 and other genotoxic carcinogens (Chen et al, 2010;Woo et al, 2011). However, little is known about the numbers and types of mutations that are present in the liver over the extended period required for the development of HCC.…”

Como Os Clusters Industriais Em Operações E Logística São Abordados

“…Sendo assim, é essencial direcionar corretamente a equipe e saber trabalhar bem todos os imprevistos que possam vir a ocorrer durante o percurso. (Joslin & Müller, 2015) Para medir a eficiência do projeto por meio de diferentes pontos de vista (Shenhar, Dvir, Levy, & Maltz, 2001) Gráfico 1 -Sucesso do projeto quanto ao prazo Fonte: Adaptada de (Shenhar et al, 2001) A pressão para que os negócios incorporem os princípios do desenvolvimento sustentável vem aumentando dentre as políticas e atividades da empresa. O gerenciamento de gerenciamento de projetos não é diferente, cada vez mais a forma como são praticados devem se alinhar a esse conceito exigido pelos stakeholders.…”

AFB1‐induced mutagenesis of the gpt gene in AS52 cells

“…Several groups have recently determined mutational spectra induced by AFB 1 in bacterial reporter genes in transgenic B6C3F1 mouse liver [Chen et al 2010; Woo et al 2011]. …”