Related Experiment Videos
Biochemical toxicology of chemical teratogenesis
Abstract:
Although exposure during pregnancy to many drugs and environmental chemicals is known to cause in utero death of the embryo of fetus, or initiate birth defects (teratogenesis) in the surviving offspring, surprisingly, little is known about the underlying biochemical and molecular mechanisms, or the determinants of teratological susceptibility, particularly in humans. In vitro and in vivo studies based primarily on rodent models suggest that many potential embryotoxic xenobiotics are actually proteratogens that must be bioactivated by enzymes such as the cytochromes P450 and peroxidases such as prostaglandin H synthase to teratogenic reactive intermediary metabolites. These reactive intermediates generally are electrophiles or free radicals that bind covalently (irreversibly) to, or directly of indirectly oxidize, embryonic cellular macromolecules such as DNA, protein, and lipid, irreversibly altering cellular function. Target oxidation, known as oxidase stress, often appears to be mediated by reactive oxygen species (ROS) such as hydroxyl radicals. The precise nature of the teratologically relevant molecular targets remains to be established, as do the relative conditions of the various types of macromolecular lesions. Teratological suseptibility appears to be determined in part by a balance among pathways of maternal xenobiotic elimination, embryonic xenobiotic bioactivation and detoxification of the xenobiotic reactive intermediate, direct and indirect pathways for the detoxification of ROS (cytoprotection), and repair of macromolecular lesions. Due largely to immature or otherwise compromised embryonic pathways for detoxification, Cytoprotection, and repair, the embryo is relatively susceptible to reactive intermediates, and teratogenesis via this mechanism can occur from exposure to therapeutic concentrations of drugs, or supposedly safe concentrations of environmental chemicals. Greater insight into the mechanisms involved in human reactive intermediate-mediated teratogenicity, and the determinants of individual teratological susceptibility, will be necessary to reduce the unwarranted embryonic attrition from xenobiotic exposure.
Insights
Exposure to drugs and chemicals during pregnancy can cause birth defects. Many substances are proteratogens, requiring bioactivation into reactive metabolites that damage embryonic cells, leading to teratogenesis.
Area of Science:
- Toxicology
- Developmental Biology
- Biochemistry
Background:
- Prenatal exposure to xenobiotics can cause embryo-fetal death and birth defects.
- Mechanisms of teratogenesis and susceptibility determinants remain poorly understood, especially in humans.
Purpose of the Study:
- To elucidate the biochemical and molecular mechanisms underlying xenobiotic-induced teratogenesis.
- To identify factors influencing teratological susceptibility during embryonic development.
Main Methods:
- Review of in vitro and in vivo studies, primarily using rodent models.
- Analysis of xenobiotic bioactivation pathways involving enzymes like cytochromes P450 and prostaglandin H synthase.
- Examination of reactive intermediate formation and subsequent macromolecular damage.
Main Results:
- Many xenobiotics act as proteratogens, requiring enzymatic bioactivation to teratogenic reactive metabolites.
- These metabolites cause cellular damage through covalent binding or oxidation (oxidative stress), mediated by reactive oxygen species (ROS).
- Embryonic susceptibility is linked to imbalanced pathways of xenobiotic metabolism, detoxification, and DNA repair.
Conclusions:
- Teratogenesis often results from reactive intermediates damaging embryonic macromolecules due to immature embryonic defense mechanisms.
- Even therapeutic drug concentrations or safe environmental chemical levels can induce teratogenicity.
- Further research into human reactive intermediate-mediated teratogenicity and susceptibility is crucial for prevention.