Development of Cholesterol Homeostatic Memory in the Rat Is Influenced by Maternal Diets zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJI Spencer A. Brown, Lynette K. Rogers, J. Kay Dunn, Antonio M. Gotto, Jr, and Wolfgang Patsch The hypothesis that dietary factors in early life modify the extent of adaptive responses in adult life was tested in rats. During the gestational and lactational periods, pregnant rats were fed either a high-fat (HF) or low-fat (LF) diet (corn oil, 15% or 2%. wt/wt) until 30 days postpartum. The offspring were maintained on standard chow for an additional 100 days and fed a HF diet for I, 3, 7, or 21 days. Upon challenge for 3 days, rats born to dams fed the HF diet showed a more rapid hypercholesterolemic response when compared with rats born to dams fed a LF diet (mean k S.D.. 151 + 14 mg/dL v 122 2 6 mg/dL; P < .OOl). Higher levels of cholesterol were associated with elevated levels of apolipoprotein (ape) B (24.0 t 4 mg/dL Y 15.8 k 3 mg/dL: P < .05) and apo E (31.0 + 4 mg/dL ~24.7 k 3 mg/dL; P < .05). Further comparison of the hypercholesterolemic response between the two groups of animals showed increases in cholesterol in all major lipoprotein classes, cholesterol enrichment at the expense of triglyceride (TG) in very-low-density lipoprotein (VLDL), and elevation of apo E-containing high-density lipoprotein (HDL). Examination at longer time periods of HF challenge showed that apo E levels of the HF-exposed animals remained elevated compared with similarly challenged rats born to dams fed the LF diet (35 + 3.6 mg/dL v26 2 2.7 mg/dL; P < .05). In contrast, plasma cholesterol and apo B levels did not differ late in the course of the challenge. Our studies also suggest that the gestational period was more important than the lactational period in altering the cholesterolemic response. We conclude that expression of genes regulating cholesterol metabolism in the adult rat can be modulated by maternal diet. @ 1990 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA by zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA W. B. Saunders Company. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA E PIDEMIOLOGIC STUDIES have established the im- portance of dietary factors in the development of coronary heart disease.‘,’ Diets rich in saturated fat and/or cholesterol are associated with increased levels of plasma cholesterol and low-density lipoprotein (LDL),3,4 which are important risk factors for coronary heart disease.’ However, several studies have shown that the increase of plasma lipids in response to a cholesterol and/or high-fat (HF) challenge is highly variable even among normolipemic subjects.J,6.7 These findings in subjects without apparent disorders of lipoprotein metabolism point to subtle genetic predispositions that may become apparent only upon metabolic challenge. The contribution of maternal or neonatal dietary factors to adult lipoprotein transport have been examined by a number of experimental designs using various maternal diets, which in the rat have included the addition of cholestyramine,8,9 preweaning,” and variation in the amount of dietary choles- terol and fat,“-‘3 or fat alone.14 In such studies, the character- ization of the lipoprotein transport system has been limited to the measurement of total serum cholesterol.8-‘4 In those studies that involve metabolically challenging the adult animal, typically one test period was used.‘o.‘2.‘4 Therefore, the time course of adaptive response is not known. In search for factors influencing the heterogeneity of lipid responses to dietary challenge, we studied, in the rat, the From the Department of Medicine. Baylor College of Medicine, and The Methodist Hospital, Houston, TX. Supported in part by the Biomedical Research Support Grant of Baylor College of Medicine, Houston, TX: a grant from the Weight Watchers Foundation, Inc, Jericho, NY; and National Institutes of Health Grant No. HL-34457. Part of this research was presented at the 1987 Scientific Session of The American Federation for Clinical Research, San Diego, CA. Address reprint requests to Spencer A. Brown, PhD, Baylor College of Medicine, 6565 Fannin. Mail Station A-601, Houston. TX 77030. B 1990 by W.B. Saunders Company. 0026-0495/90/3905-0004$3.00/O 468 effect of defined maternal diets on lipid transport during later life. We report here that, in mature animals, the response of plasma cholesterol and plasma apolipoprotein (apo) E to a HF challenge discriminates between animals born to dams fed a HF or low-fat (LF) diet.15 MATERIALS AND METHODS Animals Two different experimental protocols were used. In both protocols, only male offspring were studied to avoid confounding variables potentially caused by differences in the hormonal cycle.‘” Characterization of the cholesterolemic response. Timed- pregnant Sprague-Dawley rats (Harlan Industries and Texas Ani- mal Specialties, Houston, TX) were received at our animal facility at a gestational stage of 14 days. The rats were divided into two groups. One half of these animals were fed a custom-made HF diet containing 20% casein (wt/wt), 40% corn starch, 15% corn oil. 19.9% alphacel, 0,3% methionine, 0.2% choline bitartrate, and 4.5% mineral and vitamin mix dietary regimens (ICN Nutrition Biochem- icals, Cleveland, OH). The remaining animals were fed a LF diet containing 20% casein, 2% corn oil, 70% sucrose, 3.0% alphacel, 0.3% methionine, 0.2% choline bitartrate, and 4.5% mineral and vitamin mix (Fig 1). Pups of all mothers that gave birth within the same 24-hour period were used. For each experiment, there were a minimum of six litters per diet. At 4 days of age, the litters of each dietary group were randomized and standardized to eight pups per mother by either supplementing males or discarding females. Mothers and pups were continued on their respective diets throughout lactation until pups were weaned at 30 days of age. Females were killed and males were weighed and maintained on regular rat chow for an additional 100 days. The animals from each original dietary group were then divided into two equal subsets. One subset was fed the HF diet for 1, 3, 7, or 21 days and then killed. The other subset was maintained on standard rat chow and killed as controls on the respective days. The minimum number of animals tested for each challenge day and each maternal diet was 6. There was no difference in body weights between the two maternal dietary groups at the time of weaning (mean + SD, 75 k 4.3 g HF Y 74 f 4.0 g LF) or at the time of fat challenge (366 * 25 g HF Y 371 + 26 g LF) or after a 3-day challenge (368 + 32 g HF v 375 k 23 g LF). Metabolism, Vol39, zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQ No 5 (May), 1990: pp 468-473