Host Susceptibility Group
John (Jef) E. French, Ph.D.
Tel (919) 541-2569
Fax (919) 541-3647
P.O. Box 12233
Mail Drop K2-08
Research Triangle Park, North Carolina 27709
The Host Susceptibility Group develops new approaches that can be used to understand genetic and epigenetic differences in susceptibility to toxicity and disease. The group quantifies what they refer to as "uncertainty factors" that are associated with environmental exposure and risk and identifies quantitative trait loci through genetic analysis (meiotic mapping, haplotype-phenotype segregation analysis, etc.).
Using reverse genetic approaches, the Host Susceptibility Group aims to perform functional validation and determine the relative contribution of the candidate genes to identify their allelic variants that modify individual response to chemical exposure and disease. By doing so, we aim to identify the key genes and pathways that modify or influence an individual response – and, thus, the variance observed within a population of individuals – to chemical exposures of presumed or known risk to humans.
Using the tools of toxicology, bioinformatics and comparative genetic analysis, the identification of human orthologs of causally related animal genes will aid the extrapolation between animal models and human toxicity and disease related to environmental, occupational, and/or medicinal exposures.
Major areas of research
- Population-level range of biological response to exposure related toxicity and disease using in vitro and in vivo based models for human populations
- Genetic and/or epigenetic basis for the mechanism/mode of action of disease causing exposures
- Identify the causally related mouse genic and/or intergenic sequences for functional validation and identification of human orthologs associated with highly conserved biological pathways to aid extrapolation between species
- Aging, survival, and spontaneous disease in 10 inbred strains
- Analysis of genetic differences in absorption, distribution, metabolism (ADME) to benzene exposure, a model human toxicant and a carcinogen to identify causally related genes and their allelic variants
- Analysis of uncertainty factors and susceptibility to benzene induced genotoxicity, and hematotoxicity phenotypes in a population based study (diversity outcross mice)
- Toxicokinetic models to benzene exposure in a population of inbred mouse strains
- Experimental short-term cancer bioassays (39 weeks or less) in F1 hybrid p53 haploinsufficient inbred strains to determine haplotype susceptibility to chemical and/or ionizing radiation induced disease
- Development of an experimental model genetic analysis of ephedra/caffeine or Bis(2-chloroethoxy)methane induced cardiotoxicity and chemical disposition in multiple inbred mouse strains
- Review and evaluation of in vitro endpoints for toxicity and genotoxicity
John E. French, Ph.D., leads the Host Susceptibility Group within the Biomolecular Screening Branch of the National Toxicology Program (NTP) Division. Host Susceptibility Group members are aiding the extrapolation between animal models and human toxicity and disease.
After receiving his Ph.D. in comparative biochemistry and molecular toxicology from North Carolina State University at Raleigh, North Carolina, French pursued postdoctoral training in radiobiology at the National Naval Medical Center (NNMC) at the Armed Forces Radiobiology Institute (AFRRI) in Bethesda, Maryland. As a tenured supervisory physiologist at the AFRRI-NNMC he investigated ionizing radiation-induced toxicity and suppression of immune and xenobiotic metabolism systems in multiple model organisms. He also studies the reconstitution of radiation-ablated bone marrow or transfusion therapy with fractionated marrow cells.
As a scientist at the National Toxicology Program (NTP) and NIEHS, French has been involved in toxicology and carcinogenesis studies in laboratory rodents and genetically-modified mouse (GMM) models. In addition, he has collaborated with a number of NIEHS investigators on initiatives that included chemical and radiation induced reactive oxygen species and oxidative stress, and the use of antioxidant and caloric restriction intervention in the suppression of cancer development and implementation of the Host Susceptibility Initiative for the NTP. Currently, his work focuses on the use of multiple genetically-defined or genetically-modified inbred mouse strains for short term toxicity and cancer phenotypes with the goal of identifying quantitative trait loci of radiation and chemical carcinogen-induced DNA damage and repair in mice and humans.