Genetic factors in neurotoxicology and neuropharmacology: A critical evaluation of the use of genetics as a research tool

Abstract

Animals have evolved a detoxication system to enable them to survive in a hostile chemical environment in which foods contain many non-nutrient chemicals. Detoxication depends on enzymes which are often genetically polymorphic. As a result, inter-individual variation is common, and in humans several Mendelian loci have been identified. However, most variation in response is probably due to the action of several genes. Genetic variation in response to the neurotoxin MPTP and to chemically and physically-induced seizures is reviewed. In the former case, differences between pigmented and white mouse strains have been noted which are consistent with the hypothesis that humans are more sensitive than mice or rats because of the presence of melanin in human brains. However, variation in sensitivity probably also depends on other genes. In the case of audiogenic seizures, a single locus has been identified and mapped, but its relationship with seizures induced by other agents is not clear. Genetic variation in response to alcohol is also discussed. The failure of most toxicologists to consider genetic variation as a potentially confounding variable, and as a powerful research tool, is discussed critically in relation to non-repeatability of research on the neurotoxic effects of lead, and in relation to the genetic variation in MPTP, seizures, and alcohol response already noted. It seems clear that genetic methods provide a powerful research tool which is largely being ignored by toxicologists.

MPTP Mouse Models of Parkinson's Disease: An Update

“…Although albinism is the result of a lack of melanin pigments, the absence of melanin in mice produced by a point mutation in the gene for tyrosinase, the enzyme that catalyzes the first two steps of melanin synthesis, located on chromosome 7, did not protect the mice from MPTP-induced behavioral deficits, DA depletion in the striatum, and neuron loss in the SNpc [107]. The possibility that the higher sensitivity to MPTP observed in pigmented mice [105, 108] is caused by a susceptibility gene located in the same chromosomal region warrants further investigation.…”

Strain differences in the laboratory rat: Impact on the autonomic, behavioral, and biochemical response to cholinesterase inhibition

“…Programs of selective breeding have produced a strain or stock that has unique qualities such as sensitivity to certain drugs, pathological susceptibility, and other sequelae (Festing, 1993). To this end, Festing (1991) suggested that inbred strains are genetically more uniform and should exhibit a less varied response to neurotoxic agents. Isogenic inbred strains would be more amenable to toxicological screening because the genetic variation of outbred strains obscures the true treatment effects (Festing, 1986).…”

Biomarker Research in Neurotoxicology: The Role of Mechanistic Studies to Bridge the Gap between the Laboratory and Epidemiological Investigations

“…Most animal studies use only a single strain of mice or rats so that genetic variations in response are not noted; however, several studies have shown strain differences among laboratory animals in response to a wide range of xenobiotics including neurotoxic agents. For example, strain differences in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice have been reported and have been associated with differences in melanin binding or monoamine oxidase activity (40,41). Genetic influences in the developmental neurotoxicity of alcohol are also apparent (42 (51).…”