Related Experiment Videos
Metabolic activation/deactivation reactions during perinatal development
Abstract:
The role of metabolic activation/deactivation reactions during development is evaluated in relation to developmental pharmacology and toxicology. Enzyme systems evaluated include the mixed-function oxidases (aryl hydrocarbon hydroxylase and oxidative demethylation), epoxide hydration and conjugation (glutathione conjugation, sulfation, and glucuronidation). Placental transfer and milk secretion of chemicals are discussed in relation to maternal, placental, and fetal metabolism. Normal patterns of enzyme development can be modified in two ways: (1) enzyme induction and (2) enzyme imprinting. Postnatal induction of the mixed-function oxidases and glucuronyl-transferase following treatment of pregnant rats with TCDD is shown to be caused primarily by newborn exposure to TCDD in milk. Structure-activity relationship are defined for the perinatal induction of hepatic enzymes by the pure PCBs. PCBs are divided into two classes: P-450 inducers and P-448 inducers. Imprinting or programming of hepatic metabolism is a function of the sexual differentiation of enzyme activity; male and female activities are similar in prepubertal animals, whereas pronounced sex differences are evident in adults. Treatment of newborn rats (days 2--6) with diethystilbestrol or testosterone resulted in a feminization (decrease) of mixed-function oxidation and glucuronidation in adult males. No changes were seen in immature males or females or adult females. This effect appears to be irreversible and is under pituitary-hypothalamic-gonadal control. In addition to the feminization of enzyme activity, neonatal exposure to hormonally active chemicals also feminizes the hepatic response to cadmium in resultant adult animals.
Insights
Developmental exposure to certain chemicals can alter enzyme activity and metabolism in offspring. Neonatal exposure to hormones can irreversibly feminize liver enzyme responses in adult males.
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.