Biomedical Engineering Reference
In-Depth Information
changes in signal transduction or oxidative damage to DNA. Although
several studies in mice and rats have found no evidence for MeOH
carcinogenesis (NEDO, 1985, 1987), one study reported an increase in
lymphohematoreticular neoplasms in Sprague-Dawley rats exposed to
MeOH in the drinking water (Soffritti et al., 2007). The latter study was
confounded by unusual experimental conditions whereby the rat colony
had a high potential for Mycoplasma pulmonis lung infection, was not
specifically pathogen free, and had a high background level of lym-
phoma in the control animals (Soffritti et al., 2007; Cruzan, 2009). Our
studies on carcinogenic potential are discussed later in Section 7.4 on
Oxidative Stress.
7.1.4 Oxidative Stress and Other Potential Mechanisms of
Toxicity
The mechanism by which MeOH causes toxicity in the developing
embryo is not clearly understood, but one contributing factor may be
enhanced “oxidative stress,” or increased formation of ROS. These ROS
include highly toxic “free radical” intermediates such as hydroxyl
radicals that have been implicated in a number of human diseases
and drug toxicities including cancer, neurodegenerative diseases, and
birth defects (Halliwell and Gutteridge, 2007; Klaassen, 2008) (see
Section 7.4).
Using a number of models involving genetically altered animals and
drugs that enhance oxidative stress, results from our laboratory and
others have shown that ROS can adversely affect embryonic develop-
ment in at least two ways (Wells et al., 1997, 2009a, 2009b). The first
is by altering the level of signals, termed “signal transduction,” within
embryonic cells that are involved in the activation of genes, leading to
the production or suppression of proteins ultimately necessary for
normal development. The second effect of ROS is to damage cellular
macromolecules such as RNA, DNA, proteins, and lipid membranes,
resulting in their inability to perform their normal developmental role.
Other potential mechanisms in the developmental toxicity of MeOH
would include covalent binding to cellular macromolecules (RNA,
DNA, proteins) by the reactive formaldehyde metabolite, which is
