Physiological consequences of early neonatal growth retardation: effects of alpha-difluoromethylornithine on renal growth and function in the rat.
The physiological consequences of early neonatal growth retardation in the kidney were investigated using alpha-difluoromethylornithine (DFMO), a specific irreversible inhibitor of ornithine decarboxylase (ODC), a key enzyme in the biosynthesis of polyamines. We administered by s.c. 500 mg/kg/day DFMO, or saline, to Sprague-Dawley rat pups from the day of birth through postnatal day (PD) 6 and evaluated renal function on PD 4, 7, 10, and 13 using tests of basal renal clearance and urinary concentrating ability. Kidney weights and gross pathology were also obtained. On PD 39, serum chemistries and organ weights were determined. In a second experiment, we evaluated concentrating ability on PD 7-10, and basal renal function, concentrating ability, diuretic response, serum chemistries, and organ weights on PD 132-140. DFMO selectively inhibited renal growth but did not inhibit glomerular and tubular functional maturation. In fact, the rates of filtration and reabsorption (per g renal tissue), and concentrating ability were increased in treated pups. These changes were associated with long-term effects on renal function, including uremia, glucosuria, and male-specific concentrating deficits in adulthood. Several hypotheses can be developed concerning the physiological mechanisms underlying these changes (e.g., altered renal urea metabolism), which in turn may reflect either a direct role of ODC in the regulation of maturation or secondary consequences of inhibition of ODC.(ABSTRACT TRUNCATED AT 250 WORDS)
Gray
J A
JA
Perinatal Toxicology Branch, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711.
Kavlock
R J
RJ
D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000378:metabolism; D000518:Eflornithine / Q000494:pharmacology*; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D009994:Osmolar Concentration; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D013737:Testis / Q000187:drug effects / Q000254:growth & development; D014508:Urea / Q000378:metabolism; D014556:Urine
D014508:Urea; D003404:Creatinine; D000518:Eflornithine