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[Transplacental teratogenesis]
1Clinica Ostetrica e Ginecologica, Dipartimento di Scienze Ginecologiche e della Riproduzione Umana, Università di Padova.
Abstract:
Exposure during pregnancy to drugs or environmental chemicals (named xenobiotics) may cause birth defects in the embryo. Little is known about the biochemical and molecular mechanisms of teratological susceptibility. Many embryotoxic xenobiotics are proteratogens when bioactivated by enzymes, such as cytochromes, peroxidases and prostaglandin synthase to reactive intermediary metabolites. These intermediates are free radicals or electrophiles, that oxidize or bind irreversibly to cellular macromolecules such as DNA, proteins and lipids, altering cellular function. Teratological susceptibility is determined by a balance among maternal xenobiotic elimination, embryonic bioactivation and detoxification of reactive intermediates, cytoprotection and repair of molecular lesions. The embryo is relatively susceptible to reactive intermediates due to immature pathways for the detoxification, cytoprotection and repair. In this way, teratogenesis can occur from exposure to therapeutic concentrations of drugs or low concentrations of environmental chemicals.
Insights
Exposure to xenobiotics during pregnancy can cause birth defects. Embryos are susceptible due to immature detoxification and repair pathways, leading to teratogenesis from even low chemical exposures.
Area of Science:
- Biochemistry
- Toxicology
- Developmental Biology
Context:
- Pregnancy exposure to xenobiotics (drugs, environmental chemicals) can lead to embryo birth defects.
- Mechanisms underlying teratological susceptibility are not well understood.
- Many embryotoxic xenobiotics are proteratogens requiring bioactivation.
Purpose:
- To elucidate the biochemical and molecular mechanisms of teratological susceptibility.
- To explain how xenobiotic bioactivation leads to reactive metabolites.
- To outline the factors determining embryonic susceptibility to teratogens.
Summary:
- Embryotoxic xenobiotics are bioactivated by enzymes into reactive metabolites (free radicals or electrophiles).
- These metabolites damage cellular macromolecules like DNA, proteins, and lipids, disrupting cellular function.
- Embryonic susceptibility arises from immature detoxification, cytoprotection, and repair pathways, making embryos vulnerable to reactive intermediates.
Impact:
- Teratogenesis can occur even at therapeutic drug concentrations or low environmental chemical levels.
- Understanding these mechanisms is crucial for preventing birth defects.
- Highlights the vulnerability of the developing embryo to xenobiotic insult.