title: The association of increasing dietary concentrations of fish oil with hepatotoxic effects and a higher degree of aorta atherosclerosis in the ad lib.-fed rabbit.
abstract: The long-term effects of consumption of marine long-chain n-3 polyunsaturated fatty acids (PUFA) on atherosclerosis in the rabbit were examined. Female Dutch rabbits were fed purified diets, containing 40 energy% total fat, for a period of 2.5 years. To study the dose response relationship between fish oil intake and atherosclerosis, four diets were formulated with fish oil levels being 0, 1, 10 and 20 energy%. A fifth and sixth group were fed an alpha-linolenic acid-(C18:3, n-3) and linoleic acid-(C18:2, n-6) rich diet, respectively. Every 6 weeks, blood samples were taken for determination of clinical chemical parameters, triacylglycerol and total cholesterol levels. Feeding 10 and 20 energy% fish oil containing diets, resulted in an increase of liver enzymes (AST, ALT and ALP). Histological evaluation of the liver also revealed adverse effects of fish oil containing diets. Triacylglycerol blood levels were similar in all groups, and remained constant throughout the study. Total cholesterol levels in blood was significantly lower in the animals fed a linoleic acid-rich diet, as compared with the other five groups. An n-3 long-chain PUFA concentration dependent increase in aorta plaque surface area was observed in the fish oil groups. A significant positive relationship was found between the group mean score for severity of liver pathology and the aorta plaque surface area. These results indicate that the long-chain n-3 polyunsaturated fatty acids in fish oil may be hepatotoxic to the herbivorous rabbit, which may interfere with the outcome of atherosclerosis studies. This finding necessitates the exclusion of liver pathology in experimental studies on atherosclerosis in animal models.
authors.affiliation: Unilever Nutrition Centre, Unilever Research Laboratory, Vlaardingen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Ritskes-Hoitinga
authors.forename: P M
authors.initials: PM
authors.lastname: Verschuren
authors.forename: G W
authors.initials: GW
authors.lastname: Meijer
authors.forename: A
authors.initials: A
authors.lastname: Wiersma
authors.forename: A J
authors.initials: AJ
authors.lastname: van de Kooij
authors.forename: W G
authors.initials: WG
authors.lastname: Timmer
authors.forename: C G
authors.initials: CG
authors.lastname: Blonk
authors.forename: J A
authors.initials: JA
authors.lastname: Weststrate
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000139:chemically induced / Q000473:pathology*; D001835:Body Weight / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000473:pathology*; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004435:Eating; D005227:Fatty Acids / Q000032:analysis / Q000633:toxicity; D005231:Fatty Acids, Unsaturated / Q000032:analysis / Q000633:toxicity; D005260:Female; D005395:Fish Oils / Q000032:analysis / Q000633:toxicity*; D008054:Lipid Peroxides / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011817:Rabbits; D014810:Vitamin E / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D005395:Fish Oils; D008054:Lipid Peroxides; D008055:Lipids; D014810:Vitamin E