Analysis of Biomarkersof DNA Damage and Mutagenicityin Mice Exposed to Acrylonitrile
2020
Acrylonitrile
(ACN), which is a widely used industrial chemical,
induces cancers in the mouse via unresolved mechanisms. For this report,
complementary and previously described methods were used to assess
in vivo genotoxicity and/or mutagenicity of ACN in several mouse models,
including (i) female mice devoid of cytochrome P450 2E1 (CYP2E1),
which yields the epoxide intermediate cyanoethylene oxide (CEO), (ii)
male lacZ transgenic mice, and (iii) female (wild-type)
B6C3F1 mice. Exposures of wild-type mice and CYP2E1-null mice to ACN
at 0, 2.5 (wild-type mice only), 10, 20, or 60 (CYP2E1-null mice only)
mg/kg body weight by gavage for 6 weeks (5 days/week) produced no
elevations in the frequencies of micronucleated erythrocytes, but
induced significant dose-dependent increases in DNA damage, detected
by the alkaline (pH >13) Comet assay, in one target tissue (forestomach)
and one nontarget tissue (liver) of wild-type mice only. ACN exposures
by gavage also caused significant dose-related elevations in the frequencies
of mutations in the hypoxanthine-guanine phosphoribosyltransferase
(Hprt) reporter gene of T-lymphocytes from spleens
of wild-type mice; however, Hprt mutant frequencies
were significantly increased in CYP2E1-null mice only at a high dose
of ACN (60 mg/kg) that is lethal to wild-type mice. Similarly, drinking
water exposures of lacZ transgenic mice to 0, 100,
500, or 750 ppm ACN for 4 weeks caused significant dose-dependent
elevations in Hprt mutant frequencies in splenic
T-cells; however, these ACN exposures did not increase the frequency
of lacZ transgene mutations above spontaneous background
levels in several tissues from the same animals. Together, the Comet
assay and Hprt mutant frequency data from these studies
indicate that oxidative metabolism of ACN by CYP2E1 to CEO is central
to the induction of the majority of DNA damage and mutations in ACN-exposed
mice, but ACN itself also may contribute to the carcinogenic modes
of action via mechanisms involving direct and/or indirect DNA reactivity.
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