Prenatal α‐difluoromethylornithine treatment: Effects on postnatal renal growth and function in the rat

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.

Delayed Developmental Effects Following Prenatal Exposure to Drugs

“…Cases of intrauterine nephropathy have also been reported [see, e.g., 12]. The majority of human renal malformations occur sporadically, thus they are likely to have a multifactorial etiology: it is recognized that the number of nephrons in the mammalian kidney is affected by the fetal environment, as nephron deficits can be related to reduced protein synthesis [13], low protein intake [14], vitamin A deficiency [15], thyroid homeostasis [16], and in utero exposure to hyperglycemia [17] or drugs [18]. Examples of chemicals inducing severe malformations of the excretory system in experimental studies are the combination of acetazolamide-amiloride (inducing duplications of ureters and kidneys) and dimethadione, the active metabolite of trimethadione (inducing renal agenesis and shortening of ureters) [19].…”

“…It is well known that hypothalamic catecholaminergic neurons play an important role in modulating the general omeostatic response of the organism to environmental stressors, that include enhanced NE turnover at the brain level and increased levels of corticosterone and prolactin in the general circulation. Thus, central and peripheral response to restraint stress were evaluated in adult rats exposed prenatally to DZ (dose range 1-10 mg/kg) over gestational days [13][14][15][16][17][18][19][20]. Prenatal exposure to DZ altered both the brain's intrinsic response to stress (i.e.…”

Tobramycin‐induced changes in renal histology of fetal and newborn Sprague‐Dawley rats

“…No evidence of a teratogenic effect was found in rats treated with daily doses of tobramycin (TBM) up to 100 mg/kg on GD 6-15 in a conventional segment I1 study [4]. TBM, as aminoglicoside, has nephrotoxic mechanisms quite similar to those of gentamicin [5] and it was used in the present study as a model compound to assess the morphological effects on kidney development following exposure during the period of major renal organogenesis (GD [10][11][12][13][14][15][16][17][18][19]. The same parameters were also evaluated in newborns on postnatal day (PD) 9: in the Sprague-Dawley rat, from PD 7 to PD 10, the renal functional development is in a temporary plateau, therefore the impact of a transient delay would be reduced [6].…”

Fortschrittsbericht Was kann man von einer „funktionellen Pränataltoxikologie”︁ erwarten?

“…Die kritische Phase einer Organschadigung, einmal mit klinisch-funktionellen und zum anderen mit morphologischen Parametern ermittelt, uberlappt sich nicht vollstandig [30, 3 11. Nach Chlorambuzilgabe [30, 311 und 2-Difluoromethylornithin [21] variierten sie urn 4-6 Tage. Hier scheinen wir vielleicht noch vollig am Anfang zu stehen, da bei der Wahl des zeitlichen Applikationsregimes bisher immer nur von morphologischen Erkenntnissen ausgegangen wurde.…”