The teratogenicity of cadmium-metallothionein in the rat.
A single dose in the range 0.25-1.0 mg metallothionein-bound cadmium (MT-Cd)/kg body weight, when administered parenterally to the rat between day 8 and day 14 of gestation (gd 8-gd 14), is teratogenic. In vitro, the development of the isolated rat conceptus, explanted at 8.5 days of gestation, is unaffected by the addition of 1.5 microM MT-Cd to the culture medium, whereas the same concentration of ionic Cd (as CdCl2) is lethal. The incorporation of appreciable amounts of Cd into the embryo (860 pg), placenta (970 pg) and yolk sac (65.4 ng) without toxic manifestations under the former conditions suggests that the metalloprotein is incorporated pinocytotically, but without degradation, by the conceptus in vitro. It does not follow, therefore, that MT-Cd is without embryo/foetotoxicity in the pregnant rat since, in-vivo, liberation of some of the protein-bound Cd is known to occur in the blood. At short times after injection of 0.25 mg MT-Cd/kg body weight on gd 12, however, the maximal foetal and placental contents of Cd (less than 25 pg and 2 ng, respectively) are low in comparison with those after a teratogenic dose of CdCl2 and are of the same order as those in the embryo (46 pg) and placenta (100 pg) + yolk sac (3.8 ng) of the rat conceptus, cultured in the presence of the highest no-effect concentration of CdCl2 (0.065 microM). From this evidence, therefore, it is concluded that the uptake by the conceptus in vivo of either CdMT, or of Cd liberated therefrom, is unlikely to contribute to the teratogenic response. In the pregnant, as in the non-pregnant rat, the kidney appears to be the only organ that is affected directly by the metalloprotein. All doses in the range 0.25-1.0 mg MT-Cd/kg body weight are nephrotoxic and, because of this, result in prolonged anorexia in the pregnant animal. While some of the foetal deformities that occur in the CdMT-dosed animal seem to be direct consequences of the renal dysfunction, others apparently are secondary to the maternal anorexia, since they are induced in pregnant, normal rats by appropriate reductions in food intake. In rats that are injected i.p. on gd 12 with 0.25 mg MT-Cd/kg body weight, renal uptake of Cd is slower, but the final concentration is higher than in animals that are given the same dose i.v.(ABSTRACT TRUNCATED AT 400 WORDS)
Webb
M
M
Toxicology Unit, Medical Research Council Laboratories, Carshalton, Surrey, United Kingdom.
Holt
D
D
Brown
N
N
Hard
G C
GC
D000818:Animals; D002104:Cadmium / Q000493:pharmacokinetics / Q000633:toxicity*; D046508:Culture Techniques; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008668:Metallothionein / Q000633:toxicity*; D011247:Pregnancy; D011485:Protein Binding; D051381:Rats; D013723:Teratogens; D014018:Tissue Distribution
D013723:Teratogens; D002104:Cadmium; D008668:Metallothionein