Biomedical Engineering Reference
In-Depth Information
because blood formate concentrations in excess of 7-10mM have
been reported to occur in humans following ingestion of methanol
(McMartin et al., 1980; Sejersted et al., 1983).
Dorman et al. (1995) exposed pregnant CD-1 mice to methanol by
inhalation at teratogenic concentrations (10,000 or 15,000 ppm for
6 hours on GD 8) and reported no significant increase in blood or
decidual formate, indicating that formate is probably not involved in
methanol teratogenesis in the mouse. Dosing of pregnant mice by
gavage with Na
þ
-formate (750mg/kg) was neither teratogenic nor
raised maternal blood formate level. However, confirming the results
of Andrews et al. (1993a, 1995), exposure of mouse embryos to either
methanol (250mM) or Na
þ
-formate (40mM) in culture was develop-
mentally toxic.
From the studies of formate in rodents in vivo and in vitro discussed
above (Andrews et al., 1993b, 1995; Brown-Woodman et al., 1995;
Dorman et al., 1995), it appears that formate is toxic to the developing
embryo only at concentrations well in excess of those achieved after
teratogenic methanol exposure in the mouse, but within the range of
levels achieved in humans after acute high-dose methanol poisoning.
Thus, although methanol appears to be the proximate murine teratogen,
formate is still of concern in terms of potential developmental toxicity
in humans.
A series of whole embryo culture studies by Harris and coworkers
(Harris et al., 2003, 2004; Hansen et al., 2005) was designed to evaluate
the role of methanol and its metabolites in methanol-induced develop-
mental toxicity. Harris et al. (2004) showed that among methanol and its
metabolites, viability of cultured rodent embryos is most affected by
formate, while teratogenic endpoints were more sensitive to methanol
and formaldehyde. Results from these studies suggest that develop-
mental toxicity may be related to formaldehyde, as formaldehyde-
induced teratogenicity occurs at several orders of magnitude lower than
methanol (Hansen et al., 2005; Harris et al., 2004). It should also be
noted that catalase, alcohol dehydrogenase (ADH) 1, and ADH3
activities are present in the rat embryo and visceral yolk sac (VYS)
as early as 6-12 somites, which is during the early part of the culture
period (Harris et al., 2003). Thus, it is plausible that, during this
