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Prenatal alpha-difluoromethylornithine treatment: effects on postnatal renal growth and function in the rat
J A Gray1, B F Rehnberg, E H Rogers
1Developmental Toxicology Division, U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711.
Abstract:
DFMO (alpha-difluoromethylornithine) is a specific irreversible inhibitor of ornithine decarboxylase (ODC), a key enzyme in the biosynthesis of polyamines, which in turn control macromolecule synthesis during cell proliferation. The current study was designed to investigate the effects of inhibition of ODC during discrete prenatal periods on renal growth and function. We administered 5 doses of 500 mg/kg DFMO or saline s.c. to timed pregnant Sprague-Dawley rats at 12 hr intervals beginning on gestation days (GD) 11, 14, or 17. Half the dams were killed on GD 20 for fetal morphological analyses and half were allowed to go to term. Renal function was assessed on postnatal days (PD) 3, 6, 10, and 14 by tests of basal renal clearance and urinary concentrating ability, and on PD 42-44 we measured serum chemistries. All three gestational treatment regimens resulted in postnatal deficits in general growth. Only in the GD 11-13 treatment group was there evidence of embryotoxicity and neonatal renal pathophysiology. Fetal weights and urogenital morphology were altered following GD 14-16 treatment and there were persistent deficits of renal growth. GD 17-19 treatment was associated only with transient postnatal deficits of renal growth. Thus, inhibition of ODC during critical prenatal periods induced distinct developmental effects. However, there were no associations between impaired renal growth and function. These data indicate that general tissue growth is not always a predictor of physiological development and support the necessity of multifaceted approaches to the understanding of adverse developmental effects.
Insights
Alpha-difluoromethylornithine (DFMO) affects prenatal development differently based on administration timing. Early exposure caused embryotoxicity and renal issues, while later exposure led to growth deficits without functional impairment.
Area of Science:
- Developmental toxicology
- Renal physiology
- Pharmacology
Background:
- Polyamines regulate cell proliferation via macromolecule synthesis.
- Ornithine decarboxylase (ODC) is crucial for polyamine biosynthesis.
- DFMO is a specific irreversible inhibitor of ODC.
Purpose of the Study:
- To investigate prenatal ODC inhibition effects on renal development.
- To assess impacts of DFMO exposure during specific gestational periods.
- To correlate renal growth and function post-exposure.
Main Methods:
- Timed pregnant Sprague-Dawley rats received DFMO or saline on gestation days 11, 14, or 17.
- Fetal morphology and neonatal renal function were analyzed.
- Postnatal growth, renal clearance, concentrating ability, and serum chemistries were measured.
Main Results:
- All DFMO regimens caused postnatal growth deficits.
- GD 11-13 exposure led to embryotoxicity and neonatal renal pathophysiology.
- GD 14-16 exposure altered fetal morphology and caused persistent renal growth deficits; GD 17-19 exposure caused transient deficits.
- No association found between impaired renal growth and function.
Conclusions:
- Prenatal ODC inhibition timing dictates distinct developmental effects.
- General tissue growth does not always predict physiological development.
- Multifaceted approaches are needed to understand adverse developmental effects.