Effect of cadmium on bone calcium and 45Ca in mouse dams on a calcium-deficient diet: evidence of Itai-Itai-like syndrome.

To test whether Cd exposure would increase Ca release from bone during pregnancy and lactation in relation to the etiological mechanism of Itai-Itai disease, virgin female mice with 45Ca prelabeled skeletons (15 microCi/mouse) were subjected to one round of pregnancy/lactation and were exposed to a Ca-deficient diet containing 0, 5, or 25 ppm Cd or 25 ppm Pb for 32 days, from conception until Lactation Day 14. A striking loss of 45Ca was found in the dam's total skeleton (-40%), right femur (-47%), and lumbar vertebrae (L1-L5) (-75%) due only to pregnancy/lactation in conjunction with Ca deficiency. At both 5 and 25 ppm, Cd administered through food induced an additional significant 45Ca loss from the total skeleton (-25% at 5 ppm Cd, -30% at 25 ppm Cd) and right femur (39% at 5 ppm Cd, -32% at 25 ppm Cd) compared to 0 ppm animals. Almost all of the 45Ca lost from the dam's skeleton appeared in the pups, with 80% transferred via the dam's milk during lactation and only 20% transferred during gestation; a very small fraction of the dam's skeletal 45Ca was excreted. Considering stable Ca values, Cd exposure nearly doubled the loss of Ca from the dam's skeleton (-78 mg Ca/mouse at 0 ppm; -146 mg Ca/mouse at 5 and 25 ppm Cd). Paralleling 45Ca losses, a Ca-deficient diet in combination with pregnancy/lactation alone caused significant decreases in weight and mineral content of the right femur and lumbar vertebrae (dry weight, ash weight, ash/dry, Ca content, Ca/dry, and Ca/ash) (-8 to -52%). Cd at both 5 and 25 ppm showed additional decreases (-15 to -32%, Cd groups compared to 0 ppm animals). Responses were specific to Cd in that no significant effect occurred due to 32 days of Pb exposure (25 ppm). This experiment supports the view that Cd exposure in conjunction with Ca deficiency and pregnancy/lactation are key etiological factors of Itai-Itai disease and that Cd at both 5 and 25 ppm in conjunction with one round of gestation/lactation and Ca deficiency can induce an extreme demineralization characteristic of Itai-Itai-like syndrome.