Critical prenatal periods for chlorambucil-induced functional alterations of the rat kidney

Previous studies have demonstrated that exposure of rats to chlorambucil during the period of metanephric differentiation results in morphological and functional alterations of the kidneys after birth. The present study describes the effects of chlorambucil treatment at various gestational ages on neonatal renal function to determine if critical periods other than day 11 exist for inducing functional developmental toxicity of the kidneys. Groups of pregnant Sprague-Dawley rats were exposed to 4.5 mg/kg of chlorambucil on gestation days 9, 11, 13 or 15 and the offspring were evaluated for neonatal growth and viability, gross malformations of the kidneys, and renal physiology. The results demonstrate that the critical period for the induction of specific renal defects and hypoplasia lies on day 11 of gestation, but functional alterations of the kidneys were observed after exposure on day 15 of gestation. In terms of practical application, a combination of the basal clearance test and the renal concentration test together provide an efficient means for detecting prenatally induced functional alterations of the kidneys. When renal malformations or anomalies are observed in standard teratology bioassays, studies using techniques similar to those described here may be extremely useful in determining the biological significance as well as permanence or transience of effects such as renal hypoplasia, dilated renal pelvis, and dilated ureter.