Host Susceptibility Program
The National Toxicology Program (NTP) is developing a new program to
study the genetic basis for differences in susceptibility that may lead
to a better understanding of how substances in our environment may be
hazardous to some individuals and not to others. Asthma, cardiovascular
disease, cancer, diabetes, obesity, etc. are a few examples of diseases
associated with multiple interacting genes of high, intermediate, or
low penetrance that are induced or influenced by environmental exposure
to toxins.
The Host Susceptibility Program will provide the NTP with a mechanism for planning, conducting, and analyzing multi-strain animal model assessment of the acute chemical toxicity, potentially associated with a human disease or disease process (e.g., DNA damage, xenobiotic metabolism, hormonal signaling, mitochondrial energetics, etc.), as a result of genes and environment interactions. The NTP's current research and testing program evaluates acute to long term exposure to substances in isogenic strains of rats and/or mice to determine potential hazard. Through the Host Susceptibility Program, NTP scientists will take chemicals identified as toxicants in the research and testing program and evaluate them in multiple genetically diverse isogenic mouse strains to determine which strains are particularly sensitive or insensitive to the chemicals causing toxicity and associated disease.
The Host Susceptibility Program will identify critical areas of research, perform initial toxicity and phenotyping studies, and thus provide data and biological samples for further investigation through the extramural and/or intramural research programs. Ultimately, the NTP expects to learn more about the key genes and pathways involved in the toxic response and the etiology of disease mediated by substances in our environment. Such an understanding of genes and environment interactions will lead to more specific and targeted research and testing strategies for the NTP scientists to use for predicting the potential toxicity of substances in our environment and their presumptive risk to humans and disease susceptibility.
Request for Information
Requests for information were advertised through both the NIH Guide for Grants and Contracts (http://grants.nih.gov/grants/guide/notice-files/NOT-ES-07-009.html) and the Federal Register (Vol. 72, p.56358) to describe the development of an new research program as described above. In addition, the request was disseminated online through list servers of major biomedical research organizations. Twenty-seven individual responses were received from 21 major institutions and private citizens. From this data, all respondents from major research institutions (25/25) supported the incorporation of genetic variation in both in vivo and in vitro (cell based) models for environmental and medical safety evaluations. They noted the uncertainty of interspecies differences and documented differences between species. However, a number indicated the potential to use humanized mice on different genetic backgrounds to overcome species differences. A majority of respondents also supported the need to evaluate xenobiotics of public health importance and to design research and testing protocols that provide data that inform and characterize human relevance. Genome wide studies were cited that allow genetic and epigenetic variables to be investigated that identify system level pathways and biomarker of exposure and effect are critical to environmental health research. In addition, a number indicated that support for development of resource centers to provide infrastructure for large scale laboratory rodent studies, bioinformatics, single nucleotide polymorphisms and gene copy number variation, and statistical support is critical to this area of research and testing. This data has been carefully analyzed and is critically important to the development and implementation of this program.
Contact information
The Host Susceptibility Program will provide the NTP with a mechanism for planning, conducting, and analyzing multi-strain animal model assessment of the acute chemical toxicity, potentially associated with a human disease or disease process (e.g., DNA damage, xenobiotic metabolism, hormonal signaling, mitochondrial energetics, etc.), as a result of genes and environment interactions. The NTP's current research and testing program evaluates acute to long term exposure to substances in isogenic strains of rats and/or mice to determine potential hazard. Through the Host Susceptibility Program, NTP scientists will take chemicals identified as toxicants in the research and testing program and evaluate them in multiple genetically diverse isogenic mouse strains to determine which strains are particularly sensitive or insensitive to the chemicals causing toxicity and associated disease.
The Host Susceptibility Program will identify critical areas of research, perform initial toxicity and phenotyping studies, and thus provide data and biological samples for further investigation through the extramural and/or intramural research programs. Ultimately, the NTP expects to learn more about the key genes and pathways involved in the toxic response and the etiology of disease mediated by substances in our environment. Such an understanding of genes and environment interactions will lead to more specific and targeted research and testing strategies for the NTP scientists to use for predicting the potential toxicity of substances in our environment and their presumptive risk to humans and disease susceptibility.
Request for Information
Requests for information were advertised through both the NIH Guide for Grants and Contracts (http://grants.nih.gov/grants/guide/notice-files/NOT-ES-07-009.html) and the Federal Register (Vol. 72, p.56358) to describe the development of an new research program as described above. In addition, the request was disseminated online through list servers of major biomedical research organizations. Twenty-seven individual responses were received from 21 major institutions and private citizens. From this data, all respondents from major research institutions (25/25) supported the incorporation of genetic variation in both in vivo and in vitro (cell based) models for environmental and medical safety evaluations. They noted the uncertainty of interspecies differences and documented differences between species. However, a number indicated the potential to use humanized mice on different genetic backgrounds to overcome species differences. A majority of respondents also supported the need to evaluate xenobiotics of public health importance and to design research and testing protocols that provide data that inform and characterize human relevance. Genome wide studies were cited that allow genetic and epigenetic variables to be investigated that identify system level pathways and biomarker of exposure and effect are critical to environmental health research. In addition, a number indicated that support for development of resource centers to provide infrastructure for large scale laboratory rodent studies, bioinformatics, single nucleotide polymorphisms and gene copy number variation, and statistical support is critical to this area of research and testing. This data has been carefully analyzed and is critically important to the development and implementation of this program.Contact information
For questions or additional information contact:
Dr. John E. French
Host Susceptibility Branch
National Toxicology Program
NIEHS/NIH
P.O. Box 12233, MD K2-08
Research Triangle Park, NC 27709
T: (919) 541-2569
Web page last updated on September 23, 2009
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