Keenan K P, Soper K A, Hertzog P R, Gumprecht L A, Smith P F, Mattson B A, Ballam G C, Clark R L
Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Toxicol Pathol. 1995 May-Jun;23(3):287-302. doi: 10.1177/019262339502300306.
This study compared the effects of ad libitum (AL) overfeeding and moderate dietary restriction (DR) of 2 different diets on Sprague-Dawley (SD) rat survival and spontaneous, age-related proliferative and degenerative lesions. SD rats were fed Purina Rodent Chow 5002 or a modified Rodent Chow 5002-9 containing lower protein, fat, metabolizable energy, and increased fiber by AL or by DR at 65% of the AL amount by measurement or time (6.5 hr). At 106 wk, rats fed the 5002-9 diet AL did not have significantly improved survival over rats fed the 5002 diet AL. The 5002 diet fed DR by time (6.5 hr) improved survival for males but not females. Only DR by measurement of both diets resulted in lower mortality for both sexes. By 106 wk rats fed either diet by AL had the same brain weights as DR fed rats, but AL fed rats had greater body weight, body fat content, and increased heart, lung, kidney, liver, adrenal, thyroid, and pituitary weights that correlated with an increased incidence and severity of degenerative and/or proliferative lesions in these organs. Moderate DR delayed the progression of chronic nephropathy by delaying the early development of glomerular hypertrophy that initiates the development of glomerular sclerosis and nephron loss in AL overfed rats. Moderate DR lowered the incidence, severity, and progression of cardiomyopathy and other degenerative, age-related lesions and appeared to delay the development of reproductive senescence in SD females. The conclusion from this study is that moderate DR delayed onset and progression of degenerative lesions, and death due to cardiovascular or renal disease, and thus potentially improves the bioassay to detect compound-specific chronic toxicity.
本研究比较了随意采食（AL）过量喂养和适度饮食限制（DR）两种不同饮食对斯普拉格-道利（SD）大鼠存活率以及自发性、与年龄相关的增殖性和退行性病变的影响。SD大鼠通过AL或按测量值或时间（6.5小时）以AL量的65%进行DR，分别喂食普瑞纳啮齿动物饲料5002或改良的啮齿动物饲料5002-9，后者蛋白质、脂肪、可代谢能量含量较低，纤维含量增加。在106周时，与喂食5002饲料AL的大鼠相比，喂食5002-9饲料AL的大鼠存活率没有显著提高。按时间（6.5小时）对5002饲料进行DR可提高雄性大鼠的存活率，但对雌性大鼠无效。只有按测量值对两种饲料进行DR才能降低两性的死亡率。到106周时，通过AL喂食任一饲料的大鼠脑重与通过DR喂食的大鼠相同，但通过AL喂食的大鼠体重更大、体脂含量更高，心脏、肺、肾脏、肝脏、肾上腺、甲状腺和垂体重量增加，这与这些器官中退行性和/或增殖性病变的发生率和严重程度增加相关。适度的DR通过延缓肾小球肥大的早期发展来延缓慢性肾病的进展，而肾小球肥大是AL过量喂养大鼠中肾小球硬化和肾单位丢失发展的起始因素。适度的DR降低了心肌病以及其他退行性、与年龄相关病变的发生率、严重程度和进展，并似乎延缓了SD雌性大鼠生殖衰老的发展。本研究的结论是，适度的DR延缓了退行性病变的发生和进展，以及心血管或肾脏疾病导致的死亡，从而有可能改善检测化合物特异性慢性毒性的生物测定法。
