Effect of lithium carbonate on mouse and rat embryos in vitro

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Abstract
Lithium is effective in the treatment of manic‐depressive psychosis but is suspected to be a developmental toxicant in humans. It is a developmental toxicant in mice and rats in vivo, but at human therapeutic serum levels of 0.6–1.6 meq/L, rats appear to be more sensitive to the effects of the drug than do mice. The species susceptibility to lithium‐induced defects was evaluated by using a rodent whole embryo culture system employing mouse and rat embryos treated at comparable developmental stages. Mouse embryos were cultured on gestational days 8–10, and rat embryos were cultured on gestational days 10–12. Care was taken to insure that all embryos had 10 ± 2 somite pairs at the beginning of the culture period. Embryos were cultured for 44 hours in rat serum to which lithium was added to attain final drug concentrations of 0.6, 1.2, 1.8, 2.4, or 5.0 meq/L. Control embryos were treated with distilled water, which served as the vehicle. In rats, lithium induced significant decreases in various parameters at 1.8, 2.4, and 5.0 meq/L; no malformations were observed in rats of this stage. In mice, significant decreases occurred at 2.4 and 5.0 meq/L, and embryos treated at the highest concentration had a significantly increased frequency of open neural tubes. Rat embryos were also cultured with lithium on gestational days 9–11. The lowest dose producing developmental toxicity at this stage was 0.6 meq/L. Open neural tubes were present among younger rat embryos; however, this defect occurred in all groups, including the control group. These results suggest that there are differences in the susceptibility of mouse and rat embryos at the same developmental stage to the embryotoxic effects of lithium and that there are differences in susceptibility in rats of various developmental stages.