Mapping Gene Loci for Susceptibility to Cadmium-Induced Embryotoxicity

EPA Grant Number: R827016
Title: Mapping Gene Loci for Susceptibility to Cadmium-Induced Embryotoxicity
Investigators: Pisano, M. Michele , Berrettini, Wade H. , Greene, Robert M.
Institution: University of Louisville , University of Pennsylvania
EPA Project Officer: Reese, David H.
Project Period: September 15, 1998 through September 14, 2001
Project Amount: $600,000
RFA: Interindividual Variation in Human Susceptibility to Environmentally-caused Disease (1998) RFA Text |  Recipients Lists
Research Category: Health Effects , Health

Description:

The objective of the present application is to utilize Quantitative Trait Loci (QTL) mapping methods to identify the chromosomal location of genes which contribute to the differential sensitivity of inbred mouse strains to cadmium-induced embryotoxicity. These studies will not only elucidate the molecular genetic basis of cadmium-induced mammalian embryotoxicity, but will establish a precedent for the utility of QTL mapping techniques in identifying genes conferring susceptibility to other reproductive and developmental toxicants found in the environment/workplace.

Approach:

In order to accomplish the proposed objective of identifying gene loci conferring susceptibility cadmium-induced embryotoxicity in inbred mouse strains, three Specific Aims have been evolved. Studies proposed in Specific Aim #1 will establish the range of variance in developmental susceptibility to cadmium-induced limb defects using a panel of twelve inbred strains of mice. Since the mapping of susceptibility genes by the QTL strategy works optimally when using two genetically distinct inbred (parental) strains which differ by two standard deviations or more in the quantitative trait under study, this initial strain survey will identify two those inbred mouse strains manifesting the greatest difference in susceptibility to cadmium-induced limb dysmorphology, and will provide a comprehensive database documenting the visceral, skeletal and gross abnormalities elicited by in utero cadmium exposure in twelve mouse strains. Studies outlined in Specific Aim #2 will optimize the cadmium dose-response relationship for production of limb defects in the two mouse strains with the greatest difference in sensitivity to cadmium*s embryotoxic effect. Lastly, studies proposed in Specific Aim #3 will utilize a QTL mapping strategy to identify the gene loci that confer susceptibility to cadmium-induced limb defects. A population of cadmium-exposed fetuses from F1 cross and F2 intercross generations will be quantitatively phenotyped for limb defect, samples of DNA from the F2 generation fetuses will be collected, and the fetal DNAs will be used for DNA microsatellite mapping and linkage analyses in order to identify those loci contributing toward susceptibility to cadmium's toxic effects on the limb.

Expected Results:

These studies will not only elucidate the molecular genetic basis of mammalian embryotoxicity, but will establish a precedent for the utility of QTL mapping techniques in identifying genes conferring susceptibility to other reproductive and developmental toxicants found in the environment/workplace. Since QTL Mapping techniques are applicable to any phenomenon that is due in part to heritable factors, the advantage of these techniques over traditional gene mapping techniques is that they can be utilized to identify the gene loci that contribute significantly to phenotypic variation within and between populations or species and hence are of utility in identifying gene loci that confer differences in susceptibility to the induction of reproductive or developmental anomalies. Currently, few if any "susceptibility" biomarkers are available for environmental risk assessment. In order to create diagnostic biomarkers to screen for individuals at increased risk of adverse reproductive outcomes following environmental/occupational exposure to environmental toxins, one must first identify the gene loci or genetic polymorphisms conferring differential susceptibility of the organism to the toxic effects of these agents. Studies such as those proposed in the current application provide a novel approach to mapping such susceptibility genes in mammalian populations.

Supplemental Keywords:

developmental toxicology., RFA, Health, Scientific Discipline, Genetics, Health Risk Assessment, Susceptibility/Sensitive Population/Genetic Susceptibility, Environmental Microbiology, Risk Assessments, genetic susceptability, Molecular Biology/Genetics, Biology, interindividual variability, molecular epidemiology, dose-response models, biomarkers, Quantitative Trait Loci, genetic predisposition, mapping gene loci, gene mapping, animal models, human exposure, environmentally caused disease, human susceptibility, cadmium induced embryotoxicity