Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Experiment Videos

Genetic aspects of toxicity during development

D W Nebert, S S Thorgeirsson, G H Lambert

    Environmental Health Perspectives
    |December 1, 1976
    PubMed
    Summary

    The Ah locus in mice influences detoxification enzymes, affecting fetal development and drug toxicity. Genetic variations in aromatic hydrocarbon responsiveness impact susceptibility to developmental toxicity and acetaminophen-induced liver damage.

    Related Concept Videos

    You might also read

    Related Articles

    Articles linked to this work by shared authors, journal, and citation graph.

    Sort by
    Same author

    Glutathione defense mechanism in liver injury: insights from animal models.

    Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association·2013
    Same author

    Erratum to: Perceptions of genetic research in three rural Appalachian Ohio communities.

    Journal of community genetics·2012
    Same author

    Personalized medicine: temper expectations.

    Science (New York, N.Y.)·2012
    Same author

    Effect of vitamin C deficiency during postnatal development on adult behavior: functional phenotype of Gulo-/- knockout mice.

    Genes, brain, and behavior·2012
    Same author

    Recommendations for locus-specific databases and their curation.

    Human mutation·2007
    Same author

    A structured simple form for ordering genetic tests is needed to ensure coupling of clinical detail (phenotype) with DNA variants (genotype) to ensure utility in publication and databases.

    Human mutation·2007

    Area of Science:

    • Pharmacology
    • Toxicology
    • Genetics

    Background:

    • The Ah locus regulates cytochrome P1-450 and associated monooxygenase activities, crucial for metabolizing foreign chemicals and endogenous substrates.
    • Cytochrome P1-450 enzymes play a role in potentiating and detoxifying various compounds, with different P450 forms producing distinct reactive intermediates.
    • Genetic variations in the Ah locus can be identified early and influence an organism's response to environmental factors and xenobiotics.

    Purpose of the Study:

    • To investigate the role of the Ah locus in mediating developmental toxicity from aromatic hydrocarbons.
    • To explore the association between Ah locus-controlled P1-450 induction and acetaminophen-induced hepatic necrosis.
    • To understand the relative resistance of fetuses and young mice to acetaminophen toxicity.

    Main Methods:

    • Utilizing genetically distinct mouse strains (C5BL/6N responsive vs. AKR/N nonresponsive) to study Ah locus effects.
    • Administering developmental toxicants (3-methylcholanthrene, 7,12-dimethylbenz[a]anthracene) to pregnant dams.
    • Examining acetaminophen-induced hepatic necrosis in relation to glutathione levels, drug metabolite binding, and P1-450 induction.

    Main Results:

    • Developmental toxicity, including stillbirths and malformations, was associated with genetically mediated aromatic hydrocarbon responsiveness.
    • Acetaminophen-induced hepatic necrosis correlated with glutathione depletion, covalent binding of metabolites, and Ah locus-controlled P1-450 induction.
    • Fetuses and young mice (≤10 days old) exhibited relative resistance to acetaminophen-induced glutathione depletion and subsequent hepatic necrosis.

    Conclusions:

    • The Ah locus is a critical genetic determinant of susceptibility to both developmental toxicity and drug-induced organ damage.
    • Understanding Ah locus variations is vital for predicting individual responses to environmental pollutants and therapeutic agents.
    • Age-dependent resistance mechanisms in neonates warrant further investigation regarding xenobiotic metabolism and detoxification pathways.

    Related Experiment Videos