Teratogenic Effect of Lithium Carbonate in Early Development of Balb/C Mouse

Abstract

Lithium carbonate is used as a standard treatment for manic depression. While researchers have investigated the teratogenic effects of lithium carbonate on embryos of various animals in later stages of development, very limited work has been done on the probability of effects at early stages of development. In this study, the teratogenic effect of lithium carbonate was investigated at earlier preimplantation through implantation stages of development of Balb/C mouse embryos. A therapeutic dose (i.e., 300 mg/kg b.w.) was injected into mice intraperitoneally on days 3.5, 4.5, 5.5, and 6.5 of pregnancy. Then, on day 15.5 of gestation, embryos were collected from the pregnant animals. Among the embryos, 71.7% were healthy, 10.7% resorbed, 3.1% showed lordosis, 8.1% were underdeveloped and 8.4% had eye malformations. Significant increases (P < 0.05) in the number of hepatic megakaryocytes and nucleated red cells were also observed among experimental embryos. Analysis of maternal serum proteins prepared from dissected animals showed a significant increase or decrease (P < 0.05) in the levels of serum proteins albumin, a2 globulin, b globulin, and g globulin. This research on early developmental stages suggests that pregnant mothers need to be aware of possible teratogenic effects at early stages of pregnancy, although it has been thought that the egg envelope can prevent teratogens from entering. In this case, mothers may need to stop lithium carbonate treatment before they make a decision to become pregnant.

Chronic lithium administration in a mouse model for Krabbe disease

“…Moreover, this approach should be carefully evaluated, because of the known side effect of lithium carbonate to cause teratogenicity during early development in animal models. 66 The most serious side effect of lithium on nervous system development is the formation of neural tube defects (NTDs), including myelomeningocele, anencephaly, and encephalocele, but the occurrence rate and susceptibility to NTDs in mice exposed to lithium are significantly influenced by the uptaken dose of the drug and by the mouse strain. 67 Currently, many therapeutic approaches for KD are currently under pre-clinical studies, as GT (mainly based on adeno-associated vector), 36,68 chaperone-mediated therapies, 11 or nanovector-mediated ERT.…”

“…Indeed, the possibility that KD is diagnosed before symptoms onset in humans is very rare. Moreover, this approach should be carefully evaluated, because of the known side effect of lithium carbonate to cause teratogenicity during early development in animal models 66 . The most serious side effect of lithium on nervous system development is the formation of neural tube defects (NTDs), including myelomeningocele, anencephaly, and encephalocele, but the occurrence rate and susceptibility to NTDs in mice exposed to lithium are significantly influenced by the uptaken dose of the drug and by the mouse strain 67 …”

Lithium‐induced overexpression of β‐catenin delays murine palatal shelf elevation by Cdc‐42 mediated F‐actin remodeling in mesenchymal cells

“…A previous study reported that the recommended human therapeutic serum lithium concentration was 0.6–1.6 milliequivalents/l, and the lethal concentration was 4.5 milliequivalents/l (Szabo, 1970). While the effect of human fetal lithium exposure on cleft palate appears little known (Nokhbatolfoghahai & Parivar, 2010; Yonkers et al, 1998), animal studies have documented lithium‐induced embryotoxicity (Giles & Bannigan, 1997; Nokhbatolfoghahai & Parivar, 2010; Yonkers et al, 1998). However, the molecular mechanisms of lithium teratogenicity have not previously been clarified, especially in palatogenesis (Nokhbatolfoghahai & Parivar, 2010).…”

“…The mechanism by which lithium acts as a developmental toxicant for cleft palate remains unclear (Nokhbatolfoghahai & Parivar, 2010). However, it is known that Lithium often activates canonical Wnt/β‐catenin signal pathway for inhibiting GSK‐3β protein, which disrupts the β‐catenin destruction complex.…”