HEPATIC LEVELS OF CADMIUM, ZINC AND COPPER IN MULTIPAROUS, NULLIPAROUS AND OVARIECTOMIZED MICE FED EITHER A NUTRIENT-SUFFICIENT OR NUTRIENT-DEFICIENT DIET CONTAINING CADMIUM

As a simulation of etiological factors known for Itai-Itai disease, fe male mice were subjected to the individual and combined stresses of di etary cadmium, nutrient-deficient diet, multiparity and ovariectomy. F rom age 68 days, female mice were maintained on either nutrient-suffic ient (+) or -deficient (-), purified diets containing either 0.25 (env ironmental), 5, or 50 ppm Cd as CdCl2; the nutritional composition of (-) diet simulated that of food consumed by Japanese women who contrac ted Itai-Itai disease. At age 70 days, half of the mice began a breedi ng regimen of six consecutive, 42-day rounds of pregnancy/lactation (P L mice); the remainder were maintained as virgin, non-pregnant control s (NP mice). Limited numbers of PL and NP mice were sacrificed at the end of each reproductive round. PL(+) mice taken in a given round had successively borne litters in that round and all preceding ones. PL(-) females taken at the end of round (R)-1, -2 and -3 had successively b orne litters through those rounds; those taken at the end of R-5 or -6 had nonsuccessively borne litters in four of five or three of six rou nds, respectively. At the end of the 252-day reproductive period, rema ining females entered the 392-day, post-reproductive phase of the expe riment. At age 546 days (mid-R-12), PL females having successfully bor ne at least three litters were ovariectomized (OV) to mimic human meno pause, while NP females were either ovariectomized or sham-operated (S O). After surgery, all females were maintained to age 714 days (mid-R- 16), then sacrificed. Food consumption, monitored on a weekly basis ov er the first nine rounds, was in general not significantly affected by dietary Cd level or nutrient deficiencies for females of the same rep roductive status; consumption was increased about 2.5-fold in PL versu s NP groups during the reproductive period and about 1.4-fold during t he post-reproductive period. Over the reproductive period, small incre ases in liver concentrations of Zn and Cu were observed (cal 3.1- and 2.5-fold, respectively) with far larger increases for Cd (ca. 22200-fo ld). Threshold hepatic Cd concentrations below which the concentration s of Zn and Cu were relatively constant and independent of Cd concentr ation were identified; they were 2.7 mu g Cd/g liver for Zn and 3.3 mu g Cd/g liver for Cu for females consuming (+) diet, and 4.9 mu g Cd/g liver for Zn and 4.5 mu g Cd/g liver for Cu for females consuming (-) diet. Regardless of Cd exposure level, round-by-round hepatic concent rations of Cd were generally 2- to 6-fold higher in PL than NP mice, w hile Zn or Cu levels were generally only 1.1- to 2.5-fold higher. For each reproductive round, hepatic concentrations of Cd in NP females we re consistently about 10-fold greater in mice exposed to 50 than 5 ppm dietary Cd; corresponding Zn levels were essentially equivalent. For PL females, Cd levels were about 7-fold greater in 50 than 5 ppm Cd-ex posed groups, however Zn concentrations were about 45% decreased. The pattern of Cd, Zn and Cu sequestration established during the reproduc tive period clearly differed from that of the post-reproductive period . Between R-6 and -16, hepatic concentrations of Cd, Zn and Cu appreci ably decreased (14-69%) in 5 ppm Cd-exposed NPOV and PLOV females rega rdless of diet-type consumed. At the 50 ppm Cd level, Cd and Zn concen centrations dramatically rose with increases in Cd (37-129%) exceeding those of Zn (12-21%). (C) 1997 Elsevier Science Ireland Ltd.