跳至主要内容

Diversity Outbred mice better predict potential human responses to chemical exposures

A genetically diverse mouse model is able to predict the range of response to chemical exposures that might be observed in human populations, researchers from the National Institutes of Health have found. Like humans, each Diversity Outbred mouse is genetically unique, and the extent of genetic variability among these mice is similar to the genetic variation seen among humans.
Using these mice, researchers from the National Toxicology Program (NTP), an interagency program headquartered at the National Institute of Environmental Health Sciences (NIEHS), were able to identify specific genes or chromosomal regions that make some mice more susceptible, and others more resistant, to the toxic effects of benzene. Benzene is a common air pollutant and human carcinogen found in crude oil, gasoline, and cigarette smoke, and naturally produced by wildfires and volcanoes.
The scientists found that, like humans, each Diversity Outbred mouse developed at The Jackson Laboratory, Bar Harbor, Maine, responded to the effects of the chemical exposure differently. Exposure responses were assessed by measuring the frequency of micronucleated red blood cells, a biological marker of chromosomal damage, which is a hallmark of benzene exposure. The researchers measured the levels of this biomarker in each mouse before and after exposure.
Some mice demonstrated extraordinary sensitivity to the exposure, while others showed no response. The range of response from lowest to highest was approximately 5-fold. Since the researchers knew the genetic makeup of each mouse, they could pinpoint the regions involved in susceptibility or resistance to the chemical exposure, and then look for related genetic regions in human chromosomes.
A graph showing how mice react to benzene exposure.

Because each mouse is genetically different, each responds uniquely to benzene exposure. 
“This paper points out the significant genetic differences that are found throughout every population that must to be taken into account when extrapolating data from animals to humans,” said Linda Birnbaum, Ph.D., director of NTP and NIEHS. “The Diversity Outbred mouse is a useful model for predicting the range of response that might be observed in humans following exposure to a chemical.”
Benzene was selected by NTP as a case study for testing the mouse model, because there is an abundance of animal and human toxicity data for comparison. Benzene can affect people differently, depending on the level and duration of exposure, making it important to accurately estimate the levels at which it may cause harm to the most susceptible individuals.
“These genetically diverse mice provided a reproducible response to benzene exposure across two independently exposed groups, suggesting that each group of genetically unique mice demonstrated the same range of differential susceptibility, much like what you would find in human epidemiology studies,” said Jef French, Ph.D., lead author on the paper. “It’s important to be able to accurately measure the impact of exposure and to develop appropriate permissible safety levels for toxic compounds. This model can help us do that with greater accuracy.”
These results may lead to further research to better understand genetically regulated responses to toxicity in humans, as well as mechanisms of susceptibility and resistance to environmental exposures as they relate to disease. “In addition to informing the design of human epidemiology studies evaluating associations between chemical exposures and biological effects in diverse populations, the Diversity Outbred mouse model may also provide valuable data for use by regulators and manufacturers conducting chemical risk assessments,” said co-author Kristine Witt of NTP.
The paper is available online in the journal Environmental Health Perspectives. In addition to NIEHS and NTP, researchers from The Jackson Laboratory, ILS Inc., and Alion Science and Technology Corporation also collaborated in the research effort. The National Institute of General Medical Sciences, part of NIH, also helped support the study (grants P50GM076468 and R01GM070683).
Next spring, the NIEHS Division of Extramural Research and Training plans to hold a meeting to look at the Diversity Outbred mouse model and other population-based rodent models that can be used to advance the field of environmental health sciences.
Reference: French JE, Gatti DM, Morgan DL, Kissling GE, Shockley KR, Knudsen GA, Shepard KG, Price HC, King D, Witt KL, Pedersen LC, Munger SC, Svenson KL, Churchill GA. 2014. Diversity Outbred mice identify population based exposure thresholds and genetic factors that influence benzene-induced genotoxicity. Environ Health Perspect: doi: 10.1289/ehp.1408202.
NIEHS supports research to understand the effects of the environment on human health and is part of NIH. For more information on environmental health topics, visit http://www.niehs.nih.gov. Subscribe to one or more of the NIEHS news list to stay current on NIEHS news, press releases, grant opportunities, training, events, and publications.
NTP is a federal, interagency program, headquartered at the NIEHS, whose goal is to safeguard the public by identifying substances in the environment that may affect human health. For more information about NTP and its programs, visit http://ntp.niehs.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
NIH...Turning Discovery Into Health®
Reference
French JE, Gatti DM, Morgan DL, Kissling GE, Shockley KR, Knudsen GA, Shepard KG, Price HC, King D, Witt KL, Pedersen LC, Munger SC, Svenson KL, Churchill GA. 2014. Diversity Outbred mice identify population based exposure thresholds and genetic factors that influence benzene-induced genotoxicity. Environ Health Perspect: doi: 10.1289/ehp.1408202.
###

评论

发表评论

此博客中的热门博文

Medicilon and Binhui Biopharmaceutical Have Reached a Strategic Collaboration to Jointly Draw a New Blueprint for the Development of New Biological Drugs

  On March 18, Medicilon and Binhui Biopharmaceutical (Binui Bio) announced a strategic collaboration.  The two parties will work together to jointly explore the possibilities in cutting-edge fields such as oncolytic viruses, nucleic acid drugs and protein drugs. Gather and Work Together to Create Advantages      Facilitate the Research and Development of Oncolytic Viruses, Nucleic Acids, Proteins and Other Drugs As a one-stop biopharmaceutical comprehensive preclinical R&D service CRO, Medicilon has been developing and accumulating for 20 years, always adhering to the spirit of innovation, and has successfully constructed bi/multi-specific antibodies,  ADCs ,  mRNA vaccines ,  small nucleic acid drugs ,  PROTAC , and  CGT technical service platform  that have helped 421 INDs obtain clinical approval.  It is this outstanding achievement that has earned Medicilon wide recognition in the industry and laid a solid foundation f...
发表评论
阅读全文

A Nickel-Catalyzed Reductive Alkylation of Aryl Bromides and Chlorides for Sp3-Sp2 Bond Formation

  In 2012, a nickel-catalyzed reductive alkylation method of aryl bromides and chlorides was reported. Under the optimized conditions, a variety of aryl and vinyl bromides as well as active aryl chloride can be reductively coupled with alkyl bromides in high yields. The protocols were highly functional-group tolerant and the reactions were not air or moisture sensitive. The reaction showed different chemoselectivity than conventional cross-coupling reactions. Substrates bearing both anelectrophilic and nucleophilic carbon resulted in selective coupling at the electrophilic carbon (R-X) and no reaction occurred at the nucleophilic carbon (R-[M]). The 2010 Nobel Prize in Chemistry was awarded for the Pd-catalyzed cross-coupling, and in the past decade the progress in cross-coupling has not only had a significant impact on academic research but has also influenced the industrial synthetic application. The transition-metal-catalyzed union of nucleophilic organo-boronic acids with elect...
发表评论
阅读全文

What is Toxicokinetics?

Toxicokinetics  is essentially the study of “how a substance gets into the body and what happens to it in the body”. Four processes are involved in toxicokinetics. The study of the kinetics (movement) of chemicals was originally conducted with pharmaceuticals and thus the term pharmacokinetics became commonly used. In addition, toxicology studies were initially conducted with drugs. However, the science of toxicology has evolved to include environmental and occupational chemicals as well as drugs. Toxicokinetics is thus the appropriate term for the study of the kinetics of all toxic substances. Frequently the terms  toxicokinetics ,  pharmacokinetics , or disposition may be found in the literature to have the same meaning. Disposition is often used in place of toxicokinetics to describe the time-course of movement of chemicals through the body (that is, how does the body dispose of a xenobiotic?). The disposition of a toxicant along with its’ biological reactivi...
发表评论
阅读全文