Skip to main content
Log in

Effect of lithium on rat embryos in culture: Growth, development, compartmental distribution and lack of a protective effect of inositol

  • Original Investigations
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Lithium chloride (LiCl) was tested at various concentrations (50, 100, 150 and 200 μg/ml) using a rat whole-embryo culture system beginning on gestation day 9.5 (headfold stage) in order to establish a concentration-response relationship. Open neural tubes — as described in former publications (Tesh 1988) — were not induced by lithium. A significant reduction of embryonic growth and development occurred at the lowest concentration tested (50 μg/ml). Clear-cut dysmorphogenetic effects (absence of the eye cup, kink in the spinal anläge, “blebs” at the rostral head region) occurred at a concentration of 150 μg/ml LiCl. LiCl concentrations in the embryo, visceral yolk sac, exocoelomic fluid and medium were determined after the embryos had been cultured for 48 h in the presence of a moderately embryotoxic dose of LiCl (3.5 mEq/l or 150 μg/ml). Medium supplementation withmyo-inositol in different concentrations was ineffective in antagonizing the embryotoxicity induced by LiCl.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Backstrom S (1954) Morphogenetic effects of Li on the embryonic development ofXenopus. Ark Zool 6: 527–536

    Google Scholar 

  • Bass AD, Yntema CL, Hammond WS, Frazer ML (1951) Studies on the mechanism by which sulfadiazine affects the survival of the mammalian embryo. J Pharmacol Exp Ther 101: 362–367

    PubMed  Google Scholar 

  • Berridge MJ (1986) Cell signalling through phospholipid metabolism. J Cell Sci 4 [Suppl.]: 137–153

    Google Scholar 

  • Berridge MJ, Downes CP, Hanley MR (1989) Neural and developmental actions of lithium. A unifying hypothesis. Cell 59: 411–419

    Article  PubMed  Google Scholar 

  • Breckenridge LJ, Warren RL, Warner AE (1987) Lithium inhibits morphogenesis of the nervous system but not neuronal differentiation inXenopus laevis. Development 99: 353–370

    PubMed  Google Scholar 

  • Brown NA, Fabro S (1981) Quantitation of rat embryonic development in vitro: a morphological scoring system. Teratology 24: 65–78

    Article  PubMed  Google Scholar 

  • Busa WB, Gimlich RL (1989) Lithium-induced teratogenesis in frog embryos prevented by a phosphoinositide cycle intermediate or a diacylglycerol analog. Dev Biol 132: 315–324

    Article  PubMed  Google Scholar 

  • Cockroft DL (1977) Postimplantation embryo culture. In: Neubert D, Merker H-J, Kwasigroch TE (eds) Methods in prenatal toxicology. Georg Thieme Publ., Stuttgart, pp 231–240

    Google Scholar 

  • Cockroft DL (1979) Nutrient requirements of rat embryos undergoing organogenesis in vitro. J Reprod Fert 57: 505–510

    Google Scholar 

  • Cockroft DL (1988) Changes with gestational age in the nutritional requirements of postimplantation rat embryos in culture. Teratology 38: 281–290

    Article  PubMed  Google Scholar 

  • Drummond AH (1987) Lithium and inositol lipid-linked signalling mechanisms. TIPS 8: 129–133

    Google Scholar 

  • Edmonds LD, Oakley GP (1990) Ebstein's anomaly and maternal lithium exposure during pregnancy. Teratology 41: 551

    Google Scholar 

  • Ehrlich BE, Diamond JM (1980) Lithium, membranes, and manic-depressive illness. J Membrane Biol 52: 187–200

    Article  Google Scholar 

  • Garcia-Palmer F, Weigensberg M, Freinkel N (1988) Lithium (Li+) and the early postimplantation embryo: embryotoxicity and changes in myo-inositol metabolism. Clin Res 36: 482A

    Google Scholar 

  • Gralla EJ, McIlhenny HM (1972) Studies in pregnant rats, rabbits and monkeys with lithium carbonate. Toxicol Appl Pharmacol 21: 428–433

    Article  PubMed  Google Scholar 

  • Hansen DK, Walker RC, Grafton TF (1990) Effect of lithium carbonate on mouse and rat embryos in vitro. Teratology 41: 155–160

    Article  PubMed  Google Scholar 

  • Herbst C (1892) Experimentelle Untersuchungen über den Einfluss der veränderten chemischen Zusammensetzung des umgebenden Mediums auf die Entwicklung der Tiere. Z Wiss Zool 55: 446–578

    Google Scholar 

  • Jacobsen SJ, Jones K, Johnson K, Ceolin L, Kaur P, Sahn D, Donnenfeld AE, Rieder M, Santelli R, Smythe J, Pastuszak A, Einarson T, Koren G (1992) Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester. Lancet 339: 530–533

    Article  PubMed  Google Scholar 

  • Johansen KT (1971) Lithium teratogenicity. Lancet I: 1026–1027

    Article  Google Scholar 

  • Johansen KT, Ulrich K (1969) Preliminary studies of the possible teratogenic effect of lithium. Acta Psychiatr Scand [Suppl.] 207: 91–95

    Google Scholar 

  • Jurand A (1988) Teratogenic activity of lithium carbonate: an experimental update. Teratology 38: 101–111

    Article  PubMed  Google Scholar 

  • Kallen B (1988) Comments on teratogen update: Lithium. Teratology 38: 597

    Article  Google Scholar 

  • Klug S, Lewandowski C, Neubert D (1985) Modification and standardisation of the culture of early postimplantation embryos for toxicological studies. Arch Toxicol 58: 84–88

    Article  PubMed  Google Scholar 

  • Klug S, Lewandowski C, Zappel F, Merker H-J, Nau H, Neubert D (1990) Effects of valproic acid, some of its metabolites and analogues on prenatal development of rats in vitro and comparison with effects in vivo. Arch Toxicol 64: 545–553

    PubMed  Google Scholar 

  • Loevy HT (1973) Lithium ion in cleft palate teratogenesis in CD1 nuce. Proc Soc Exp Biol Med 144: 644–646

    PubMed  Google Scholar 

  • Marathe MR, Thomas GP (1986) Embryotoxicity and teratogenicity of lithium carbonate in Wistar rats. Toxicol Lett 34: 115–120

    Article  PubMed  Google Scholar 

  • Morgan TH (1903) The relation between normal and abnormal development of the embryo of the frog, as determined by the effects of lithium chloride in solution. Wilhelm Roux' Arch Entwicklungsmech Org 16: 691–712

    Google Scholar 

  • New DAT (1978) Whole embryo culture and the study of mammalian embryos during organogenesis. Biol Rev 53: 81–122

    PubMed  Google Scholar 

  • Rana RS, Hokin LE (1990) Role of phosphoinositides in transmembrane signalling. Physiol Rev 70: 115–164

    PubMed  Google Scholar 

  • Rane A, Tomson G, Bjarke B (1974) Effects of maternal lithium therapy in a newborn infant. J Pediatr 93: 296–297

    Google Scholar 

  • Sharma A, Rawat AK (1986) Teratogenic effects of lithium and ethanol in the developing fetus. Alcohol 3: 101–106

    Article  PubMed  Google Scholar 

  • Smithberg M, Dixit PK (1982) Teratogenic effects of lithium in mice. Teratology 26: 239–246

    Article  PubMed  Google Scholar 

  • Szabo KT (1970) Teratogenic effect of lithium carbonate in the fetal mouse. Nature 225: 73–75

    PubMed  Google Scholar 

  • Tesh JM (1988) The application of whole embryo culture to new product development. Toxicol In Vitro 2: 189–194

    Article  Google Scholar 

  • Trautner EM, Pennycuik PR, Morris PJH, Gerson S, Shankly KH (1958) Effects of prolonged sub-toxic lithium ingestion on pregnancy in rats. Aust J Exp Biol Med Sci 36: 305–322

    PubMed  Google Scholar 

  • Tuchmann-Duplessis H, Mercier-Parot L (1973) Influence du lithium sur la gestation et le dévelopment prénatel du rat et de la souris. Cr Seanc Soc Biol Filiales 167: 183–186

    Google Scholar 

  • Warkany J (1988) Teratogen update: lithium. Teratology 38: 593–596

    Article  PubMed  Google Scholar 

  • Wright TL, Hoffman LH, Davies J (1970) Lithium teratogenicity. Lancet ii: 876

    Article  Google Scholar 

  • Wright TL, Hoffmann LH, Davies J (1971) Teratogenic effects of lithium in rats. Teratology 4: 151–154

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klug, S., Collins, M., Nagao, T. et al. Effect of lithium on rat embryos in culture: Growth, development, compartmental distribution and lack of a protective effect of inositol. Arch Toxicol 66, 719–728 (1992). https://doi.org/10.1007/BF01972623

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01972623

Key words

Navigation