Mutagenicity of Acrylamide and Glycidamide in the Testes of Big Blue Mice

Abstract

Acrylamide (AA) is an industrial chemical, a by-product of fried starchy foods, and a mutagen and rodent carcinogen. It can also cause damage during spermatogenesis. In this study, we investigated whether AA and its metabolite glycidamide (GA) induce mutagenic effects in the germ cells of male mice. Male Big Blue transgenic mice were administered 1.4 or 7.0mM of AA or GA in the drinking water for up to 4 weeks. Testicular cII mutant frequency (MF) was determined 3 weeks after the last treatment, and the types of the mutations in the cII gene were analyzed by DNA sequencing. The testes cII MFs in mice treated with either the low or high exposure concentrations of AA and GA were increased significantly. There was no significant difference in the cII MFs between AA and GA at the low exposure concentration. The mutation spectra in mice treated with AA (1.4mM) or GA (both 1.4 and 7.0mM) differed significantly from those of controls, but there were no significant differences in mutation patterns between AA and GA treatments. Comparison of the mutation spectra between testes and livers showed that the spectra differed significantly between the two tissues following treatment with AA or GA, whereas the mutation spectra in the two tissues from control mice were similar. These results suggest that AA possesses mutagenic effects on testes by virtue of its metabolism to GA, possibly targeting spermatogonial stem cells, but possibly via different pathways when compared mutations in liver.

Evaluation of <i>cII</i> gene mutation in the brains of Big Blue mice exposed to acrylamide and glycidamide in drinking water

“…Considering the fact that humans have larger collective lifetime exposures to AA through diet and potentially the environment (El-Ziney et al, 2009), the potential adverse health effects in humans cannot be dismissed. The magnitude of mutagenic response seen in brain tissue was different from other somatic (lung and liver) and reproductive (testis) tissues from mice exposed to same doses of AA or GA (Manjanatha et al, 2006, Wang et al, 2010. Using the same animals treated with AA or GA, we observed that only MFs in the brain (the current study) of male mice and liver (Manjanatha et al, 2006) of both male and female mice treated with high dose of AA or GA were significantly increased.…”

“…Using the same animals treated with AA or GA, we observed that only MFs in the brain (the current study) of male mice and liver (Manjanatha et al, 2006) of both male and female mice treated with high dose of AA or GA were significantly increased. On the other hand, the mutagenicity of AA or GA in testes (Wang et al, 2010) and lung (Manjanatha et al, 2015) was shown at both low and high dose groups. The reasons for the discrepancy in the mutagenic effect between the different tissues are not clear.…”

“…We previously have reported that AA and GA were mutagenic in a large variety of somatic and reproductive tissues of rodents, some of which were also the tumor target tissues (Manjanatha et al, 2006(Manjanatha et al, , 2015Mei et al, 2010;Wang et al, 2010). In addition to carcinogenic 25.0 ± 5.0 § Animals given 7.0 mM AA in drinking water manifested toxicity and therefore were removed from the chemical exposure after 3 weeks, while AA low dose and GA low and high dose treatments continued for 4 weeks.…”

“…cII Mutation spectra of brain (A), lung (B), liver (C), and testis (D) from control Big Blue mice (gray bars) and the Big Blue mice exposed to 7.0 mM AA (light gray bars) or GA (black bars). The brain spectral data came from Table 3 and the spectral data for lung, liver, and testis were from previous studies (Manjanatha et al, 2006(Manjanatha et al, , 2015Wang et al, 2010).…”

“…Briefly, we found that BB mice exposed to either AA or GA at the concentration of 1.4 and 7.0 mM in drinking water for up to 4 weeks showed significant increases in the lymphocyte Hprt mutant frequencies (MFs) and liver cII MFs only at the higher dose of 7.0 mM (Manjanatha et al, 2006). Further, we reported that the same treatment in the reproductive tissues of BB mice induced significant increases in the cII MFs in testes, with a different mutation spectrum when compared to those in liver (Wang et al, 2010). More recently we established that the same treatment protocol also led to significant induction of cII MFs in a tumor target tissue, specifically the lungs of BB mice which displayed distinct mutational spectra from control spectra, lending support for our hypothesis on the role of mutagenic processes during the development of lung carcinogenesis (Manjanatha et al, 2015).…”