Comparative pathology. Can we extrapolate from rabbits to humans?

Jelmera Ritskes-Hoitinga, Anton Wiersma*, Wim Timmer* & Gert W. Meijer*
Biomedical Laboratory, Odense University, Odense, Denmark and *Unilever Nutrition Centre, Unilever Research Laboratory, Vlaardingen, Holland.

Fish oil has been associated with reduced risk for cardiovascular disease in humans. In a long- term nutritional study, the influence of fish oil on the development of atherosclerosis and its possible toxic effects in Dutch belted rabbits was examined. The rabbit can be considered a good model for atherosclerosis studies, because - under certain experimental conditions - the character and distribution of lesions resemble those of people. (JM Jayo, 1994, The Biology of the Laboratory Rabbit, 367). All rabbits were fed cholesterol-free purified diets ad libitum with a total fat content of 40 energy%. Dietary groups 1, 2, 3 and 4 received 20, 10, 1 and 0 energy% of fish oil. Fish oil is rich in long-chain n-3 polyunsaturated fatty acids (C20:5, n-3 and C22:6, n-3). The influence of alpha-linolenic acid (C18:3, n-3) and linoleic acid (C18:2, n-6) was examined in groups 5 and 6, respectively. Because rabbits are herbivores, group 5 was included to study the effects of long-chain fatty acids from vegetable origin. Group 6 was used as the negative control group: it was known from previous studies that dietary linoleic acid reduced atherosclerosis in rabbits. The study lasted 2.5 years.
Measurements of atherosclerotic plaque surface area of the aorta showed a dose-related increase with dietary fish oil. Histological examination of the liver revealed fish oil related hepatotoxic effects. A significant positive correlation was found between group mean scores for the severity of liver pathology and group mean plaque surface areas of the aorta (R=0.96, P=0.003). In order to avoid scientific bias and reduce inappropriate future animal use, it is necessary to prevent and exclude liver pathology when atherosclerosis is being examined in animal models. It ispostulated that the herbivorous rabbit should not be used for examining the influence of dietary fish oil on atherosclerosis, in order to prevent (possible) distress which may be directly due to the dietary treatment and indirectly caused by the hepatotoxicity.
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