(Fwd) Re: Animal Models in Toxicology

George L. Wolff GWOLFF at FDANT.NCTR.FDA.GOV
Thu Feb 15 14:38:08 EST 1996


Forwarded message:
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.   













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