Maternal Clofibrate Administration Amplifies Fetal Peroxisomes

Abstract

ABSTRACT: To study the effects of peroxisome proliferators on fetal biogenesis, 400 mg/kg oral clofibrate was administered to pregnant mice beginning at d 6 of gestation. Maternal/fetal tissues from three separate experiments were harvested between gestational d 13 and 19 and maternal/fetal tissues were assayed for peroxisomal matrix, membrane-associated, and integral membrane proteins. By comparison to control pregnancies that received vehicle only, clofibrate produced a 4− to 5-fold increase in the levels of peroxisomal membrane protein 70, a 1.5− to 2-fold increase of dihydroxyacetone phosphate acyltransferase (DHAP-AT) sp act, and a 1.2− to 1.8-fold increase of catalase sp act in fetal liver of 19 d gestation. Fetal liver endoplasmic reticulum and peroxisomes were also amplified as visualized by electron microscopy. Clofibrate exhibited maximal effects on maternal tissues by 6 d of oral treatment with increases in peroxisomal membrane protein 70 occurring most clearly in maternal liver; DHAP-AT activity was increased in maternal liver, kidney, and brain but not in lung. Slight increases in DHAP-AT activities were evident in fetal brain, lung, and placenta as compared with the greater increases in liver and kidney. There was a general increase in peroxisomal proteins between 13 and 19 gestational d in all fetal tissues except placenta, and the effect of clofibrate was evident by gestational d 13 in lung and placenta. Minimal changes in the activities of acid phosphatase (lysosomal enzyme) or glycerol-3-phosphate acyltransferase (microsomal enzyme) were observed in maternal or fetal tissues although the latter enzyme was increased 10–30% by clofibrate in maternal brain, fetal lung, and placenta. The degree of amplification peroxisomal membrane portion 70 > DHAP-AT > catalase observed in several tissues after clofibrate treatment is consistent with a similar order in the sequence of peroxisomal assembly. The ability to manipulate fetal peroxisomes by maternal pharmacology provides a potentially useful system for studying the regulation of peroxisomal biogenesis.