SKELETAL CHANGES IN MULTIPAROUS, NULLIPAROUS AND OVARIECTOMIZED MICE FED EITHER A NUTRIENT-SUFFICIENT OR NUTRIENT-DEFICIENT DIET CONTAININGCADMIUM

As a simulation of the etiological factors known for Itai-Itai disease , a syndrome characterized by osteomalacia and renal dysfunction in it s Japanese victims, female mice were subjected to the individual and c ombined stresses of dietary cadmium, nutrient-deficient diet, multipar ity and ovariectomy; the calcium-depleting effect of each factor was e valuated by determining Ca levels in femur and lumbar vertebrae. At ag e 68 days, female mice were given nutrient-sufficient (+) or -deficien t (-), purified diets containing either 0.25 (environmental), 5, or 50 ppm Cd as CdCl2; the nutritional composition of (-) diet simulated th at of food consumed by Japanese victims of Itai-Itai disease. At age 7 0 days, half of the females began a breeding regimen of six consecutiv e, 42-day rounds of pregnancy/lactation (PL mice); the remainder were maintained as virgin, non-pregnant controls (NP mice). Limited numbers of PL and NP mice were sacrificed at the end of each reproductive rou nd. PL(+) mice taken at the end of round (R)-6 had successively borne litters in all six rounds, while PL(-) counterparts had nonsuccessivel y borne only three. At the conclusion of the 252-day reproductive peri od, remaining females entered the 392-day, post-reproductive phase of the experiment. At age 546 days (mid-R-12), PL females having successf ully borne at least three litters were ovariectomized (OV) to mimic hu man menopause; at the same time, NP females were either ovariectomized or sham-operated (SO). After surgery, all females were maintained to age 714 days (mid-R-16), then sacrificed. During the post-reproductive period, food consumption by females of the same reproductive status w as unaffected by elevated levels of Cd or nutrient-deficiencies in die t. However by R-16, Cd at 50 vs. 0.25 ppm had reduced body mass by 11% in both NP and PLOV females, femur and lumbar vertebral calcium conte nt (TCa) by 20 and 25% in the respective groups, and femur and vertebr al calcium/dry weight ratios (Ca/DW) by 12 and 11%. Alternative R-16 c omparisons indicated that (-) diet also diminished skeletal Ca, but th at the additional factors of (prior) multiparity and ovariectomy gener ated only small and non-significant effects. Comparison of skeletal st atus between the ends of the reproductive and post-reproductive period s indicated that (1) individual NP groups, regardless of Cd exposure, generally sustained small decreases in TCa and CaDW over time (consist ent with aging), but PL groups without exception secured significant g ains (consistent with cessation of multiparous activity), (2) skeletal integrity of PL groups was significantly more compromised by the comb ination of Itai etiological factors at the end of R-6 than R-16, and ( 3) among those factors, the most demineralizing over lifetime were chr onic exposure to Cd followed by ingestion of (-) diet. Despite these f indings, skeletal degeneration characteristic of the Itai-Itai syndrom e was ultimately not duplicated in this mouse model suggesting that th e full-blown disease required primary and profound skeletal deminerali zation secondarily supported and enhanced by renal dysfunction. (C) 19 97 Elsevier Science Ireland Ltd.