From: Self <EFS/GWOLFF>
To: drjackbud at aol.com (DrJackBud)
Subject: Re: Animal Models in Toxicology
Date: Thu, 15 Feb 1996 08:10:33
I thoroughly agree that the lack of "how" and "why" in toxicology
- especially in regard to the primitive understanding of the majority
of toxicologists of what used to be called physiological mammalian
genetics in pre-molecular days.
The choice of animal models should not necessarily be based on
the superficial resemblance of phenotypic endpoints in humans and
particular animal species, strains or genotypes. Phenotypic
resemblance does NOT imply that the molecular mechanisms leading to
those resemblances are the same or even similar in man and animal.
This is particularly true of "quantitative" disease syndromes such as
obesity, diabetes, cancer, etc. in which numerous genes are involved.
Within the last several years so several mouse genes which result
in obesity have been cloned and the proteins they specify identified.
These include ob and fat as well as agouti (which is the gene I work
with). Each gene specifies a different protein which binds to
different receptors and, presumably, affect fat metabolism/deposition
in very different ways. Which of these genes is "the best
experimental model" for human obesity?
Additionally, the background (strain) genome in which the specific
gene "does its thing" is extremely important because the gene in
question is part of a gene PATTERN which actually results in
the phenotypic endpoint.
Human obesities and other "quantitative" diseases most probably
each include a number of different syndromes with different molecular
and physiological dysregulations. Unless we can identify these, how
would we know which animal model would be most relevant to use?
In my biased opinion, until toxicologists become familiar with
some of these basic concepts of gene function and expression as they
affect the physiology and metabolism of animal models, the current
discussion can continue ad infinitum without making much progress.
The aim of this post is to provoke constructive discussion of the
genetics aspect of toxicology and animal models.
George L. Wolff, Ph.D.
Tel: (501) 543-7522
FAX: (501) 543-7635/7662
3900 NCTR Road
Jefferson, AR 72079-9502