Metabolic activation/deactivation reactions during perinatal development.

Area of Science:

• Developmental pharmacology and toxicology
• Biochemical mechanisms of xenobiotic metabolism

Background:

• Metabolic activation and deactivation reactions are crucial during development.
• Understanding these processes informs developmental pharmacology and toxicology.
• Key enzyme systems include mixed-function oxidases, epoxide hydration, and conjugation pathways.

Purpose of the Study:

• To evaluate the role of metabolic activation/deactivation reactions in development.
• To assess how maternal, placental, and fetal metabolism influence chemical transfer and secretion.
• To investigate modifications in normal enzyme development patterns, specifically enzyme induction and imprinting.

Main Methods:

• Evaluation of enzyme systems: mixed-function oxidases (aryl hydrocarbon hydroxylase, oxidative demethylation), epoxide hydration, and conjugation (glutathione, sulfation, glucuronidation).
• Analysis of placental transfer and milk secretion of chemicals.
• Investigation of enzyme induction by TCDD and PCBs in rats.
• Study of enzyme imprinting via neonatal exposure to diethylstilbestrol or testosterone in rats.

Main Results:

• Postnatal induction of mixed-function oxidases and glucuronyl-transferase in rat pups is primarily due to TCDD in milk.
• Structure-activity relationships for perinatal hepatic enzyme induction by PCBs were defined, categorizing them as P-450 or P-448 inducers.
• Neonatal exposure (days 2-6) to diethylstilbestrol or testosterone caused irreversible feminization of mixed-function oxidation and glucuronidation in adult male rats.
• Neonatal exposure to hormonally active chemicals also feminized the hepatic response to cadmium in adult animals.

Conclusions:

• Normal enzyme development patterns can be modified by induction and imprinting.
• Neonatal exposure to specific chemicals can lead to long-lasting alterations in metabolic enzyme activity and responses.
• These findings highlight the critical window of susceptibility during early development for chemical exposures.