Biomedical Engineering Reference
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embryopathies (Miller and Wells, unpublished). This interpretation is
consistent with the protective effect of PBN in reducing embryonic/fetal
DNA oxidation and the embryopathic effects of other ROS-initiating
teratogens in embryo culture and/or in vivo (Wells et al., 2009b; Lee
et al., 2011).
7.4.4 Carcinogenic Potential
7.4.4.1 Oxidatively Damaged DNA In vitro and in vivo genotoxicity
tests indicate MeOH is not mutagenic (IPCS, 1997), but carcinogenic
potential has been claimed in one controversial long-term rodent
cancer bioassay that has not been replicated (Soffritti et al., 2002). To
determine if MeOH could indirectly damage DNA via ROS-mediated
mechanisms, we treated male CD-1 mice, NZW rabbits, and cyn-
omolgous monkeys with MeOH (2.0 g/kg i.p.) and 6 hours later
assessed oxidative damage to DNA, measured as 8-oxodG formations
by HPLC with electrochemical detection. We found no MeOH-
dependent increases in 8-oxodG in bone marrow, spleen, lung, liver,
or kidney of any species (Figure 7.26) (McCallum et al., 2011a,b).
Chronic treatment of CD-1 mice with MeOH (2.0 g/kg i.p.) daily for
15 days also did not increase 8-oxodG levels in these organs. To rule
out the possibility that the lack of effect of MeOH exposure on
accumulation of oxidatively damaged DNA was due to masking by
rapid repair of induced lesions, we performed further studies in DNA
repair-deficient oxoguanine glycosylase 1 (Ogg1) KO mice. The
results were corroborated in untreated Ogg1 KO mice, which accu-
mulated 8-oxodG in bone marrow, spleen, lung, kidney, and liver with
age, but exhibited no increase following MeOH treatment, despite a
twofold increase in renal 8-oxodG in Ogg1 KO mice following
treatment with a ROS-initiating positive control, the renal carcinogen
potassium bromate (KBrO 3 ; 100mg/kg i.p.) (Figure 7.27) (McCallum
et al., 2011a,b). These observations suggest that MeOH exposure does
not promote the accumulation of oxidatively damaged DNA in lung,
kidney, or liver, and that environmental exposure to MeOH is unlikely
to initiate carcinogenesis in these organs by ROS-initiated DNA
oxidation.
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