Diversity Outbred mice better predict potential human responses to chemical exposures

November 06, 2014

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.

"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.
-end-
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 lists 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 http://www.nih.gov.

Contact:

Robin Mackar
rmackar@niehs.nih.gov
919-541-0073

NIH/National Institute of Environmental Health Sciences

Related Genetic Variation Articles from Brightsurf:

How genetic variation gives rise to differences in mathematical ability
DNA variation in a gene called ROBO1 is associated with early anatomical differences in a brain region that plays a key role in quantity representation, potentially explaining how genetic variability might shape mathematical performance in children, according to a study published October 22nd in the open-access journal PLOS Biology by Michael Skeide of the Max Planck Institute for Human Cognitive and Brain Sciences, and colleagues.

Genetic variation unlikely to influence COVID-19 morbidity and mortality
A comprehensive search of genetic variation databases has revealed no significant differences across populations and ethnic groups in seven genes associated with viral entry of SARS-CoV-2.

Researchers find pronghorn exhibit little genetic variation despite landscape obstacles
While previous research shows landscape features such as major highways restrict the daily and seasonal movements of pronghorn and increase mortality risk, this study found little, if any, evidence that these barriers affect genetic connectivity among Wyoming pronghorn.

gnomAD Consortium releases its first major studies of human genetic variation
For the last eight years, the Genome Aggregation Database (gnomAD) Consortium (and its predecessor, the Exome Aggregation Consortium, or ExAC), has been working with geneticists around the world to compile and study more than 125,000 exomes and 15,000 whole genomes from populations around the world.

Individual genetic variation in immune system may affect severity of COVID-19
Genetic variability in the human immune system may affect susceptibility to, and severity of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease (COVID-19).

Genetic variation not an obstacle to gene drive strategy to control mosquitoes
New research from entomologists at UC Davis clears a potential obstacle to using CRISPR-Cas9 'gene drive' technology to control mosquito-borne diseases such as malaria, dengue fever, yellow fever and Zika.

Genetic variation gives mussels a chance to adapt to climate change
Existing genetic variation in natural populations of Mediterranean mussels allows them to adapt to declining pH levels in seawater caused by carbon emissions.

A genetic tug-of-war between the sexes begets variation
In species with sexual reproduction, no two individuals are alike and scientists have long struggled to understand why there is so much genetic variation.

Scientists identify genetic variation linked to severity of ALS
A discovery made several years ago in a lab researching asthma at Wake Forest School of Medicine may now have implications for the treatment of amyotrophic lateral sclerosis (ALS), a disease with no known cure and only two FDA-approved drugs to treat its progression and severity.

Genetic variation contributes to individual differences in pleasure
Differences in how our brains respond when we're anticipating a financial reward are due, in part, to genetic differences, according to research with identical and fraternal twins published in Psychological Science, a journal of the Association for Psychological Science.

Read More: Genetic Variation News and Genetic Variation Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.