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

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.     

<Emphasis Type="Italic">Naja siamensis</Emphasis>, a cryptic species of venomous snake revealed by mtDNA sequencing

Because of possible variation in venom composition, an understanding of venomous snake systematics is of great importance for the optimization of antivenom treatment of snakebite patients. Intraspecific variation in the morphology of many venomous snakes complicates the definition and indentification of some species when allopatric populations are involved. Selectively neutral or near-neutral mtDNA sequences can reveal evolutionary relationships obscured by ecogenetically-caused morphological variation. We use comparative sequencing of the cytochrome oxidase subunit 1 gene to reveal the existence of a widespread, cryptic species of spiting cobra from southeast Asia. This species,Naja siamensis, is widely sympatric with other Asiatic cobra species. This may be of considerable medical significance, and calls for further research into venom composition in Asiatic cobras.     

Variability of sterol utilization in stored-products insects

A comparison of sterol utilization by 3 stored-products insects revealed very different capabilities. The fluor beetle,Tribolium castaneum dealkylates and converts dietary sitosterol to about equal amounts of cholesterol (43.7%) and 7-dehydrocholeterol (39.8%), whereas another flour beetle,Tenebrio molitor, produces considerably less 7-dehydrocholesterol (16.8%) and relatively more cholesterol (66.7%) from sitosterol. The lepidopteran,Plodia interpunctella, utilized dietary sterol very similar to plant-feeding lepidoptera, producing primarily cholesterol (86.5%) from sitosterol.     

Some citrus chitinases also possess chitosanase activities

Several acidic chitinase and chitosanase isoforms were found in 4-week-old nonembryogenic sweet orange (Valencia [Citrus sinensis (L.) Osbeck]) callus tissue. Two isoforms (designated A1-CF1 and A1-CF2) were purified to homogeneity using HPLC size exclusion, anion exchange, and chromatofocusing techniques. Both hydrolase isoforms exhibited activity with either colloidal chitin or solubilized shrimp shell chitosan. Specific activities for the purified isoforms could not be calculated because of the lack of protein and contamination of ampholytes. However, the specific activities for chitinase and chitosanase after anion exchange were respectively 404 nmol GlcNAc per min per mg protein and 2,475 nmol GlcN per min per mg protein. The M_r for both enzymes was 30,500. The homogeneous proteins cross-reacted in western blots with antiserum against a basic class I potato leaf chitinase.     

Evaluation of monoaminergic receptors in the genetically epilepsy prone rat

Summary The intensity of sound-induced convulsions in the genetically epilepsy-prone rat (GEPR) was reduced in a dose related fashion by intracerebroventricular administration of dobutamine, (₁ agonist), terbutaline (₂ agonist) or phenylephrine (₁ agonist). BHT-920 (₂ agonist) did not cause a dose-related decrease in sound-induced convulsion intensity. Binding studies showed that whole brain and receptor densities (B_max) were normal while the K_d was increased for the ligand in GEPR brain.Acknowledgment. We are most grateful to Boehringer Ingelheim for generously supplying BHT 920. We are also indebted to Ciba-Geigy Corporation for the gift of terbutaline hydrochloride and phentolamine hydrochloride. The work was supported in part by NIH grant NS 16829.