ORGAN-SPECIFIC, PROTOCOL DEPENDENT MODULATION OF 7,12-DIMETHYLBENZ[A]ANTHRACENE CARCINOGENESIS IN RAINBOW-TROUT (ONCORHYNCHUS-MYKISS) BY DIETARY ELLAGIC ACID

This study investigated pre-initiation and post-initiation effects of dietary ellagic acid (EA) on 7,12-dimethylbenz[a]anthracene (DMBA) mul ti-organ carcinogenesis in rainbow trout (Oncorhynchus mykiss). EA at 100, 250 (study 2), 1000 and 2000 (study 1) p.p.m. suppressed stomach adenopapilloma incidence by 33, 60, 70 and 78% (P less than or equal t o 0.001), respectively, as well as tumor multiplicity (P <0.01) and si ze (P <0.001) when fed continuously following DMBA initiation, However , continuous EA feeding also produced modest (250 p.p.m.) to extensive (1000, 2000 p.p.m.) growth rate suppression in these studies, Retrosp ective logistic regression modeling of the data allowed separation of growth-related from non-growth-related inhibitory effects, By this app roach: (i) tumor development showed a similarly strong dependence (sam e regression slope) on animal growth rate in all treatment groups; (ii ) EA-mediated reduction in mean population growth contributed to suppr essed stomach tumor response above 250 p.p.m. EA; and (iii) even at hi gh, toxic doses EA displayed inhibitory mechanisms additional to, and distinct from, growth suppression effect, The effects of post-initiati on EA were organ specific. Chronic EA treatment significantly suppress ed swim-bladder as well as stomach tumor incidence at doses greater th an or equal to 1000 p.p.m., but increased liver tumor incidence at dos es greater than or equal to 250 p.p.m. Three protocols examined EA eff ects on the initiation process, EA fed at 1000 p.p.m. concurrently wit h 750 p.p.m. dietary DMBA for 7 weeks modestly reduced stomach tumor i ncidence (from 85 to 78%, P <0.05) and multiplicity (from 6.3+/-4.3 to 4.9+/-2.9, P <0.01), but did not alter swim-bladder or liver response , The effect of EA pretreatment prior to DMBA single-dose initiation b y gill uptake was also examined, When fed for 1 week prior to initiati on, 2000 p.p.m. EA again imposed a small reduction in stomach adenoma incidence (from 88 to 78%; P <0.05) and multiplicity (from 5.5+/-3.2 t o 4.4+/-3.2; P <0.01). However, when EA was pre-fed for 3 weeks instea d of 1 week, protection in the stomach was lost and response in liver and swim-bladder significantly increased, In sum, these studies demons trate that EA influence on DMBA tumorigenesis in this multi-organ mode l is highly protocol dependent and organ specific, Post-initiation die tary EA consistently suppressed stomach tumor development in trout, at EA doses far lower than those required for protection in rodents. At higher doses, however, EA also displayed toxicity and a potential in s ome protocols to enhance tumor response in other organs.