Table 4.

VPA-induced malformations in experimental animals.

Authors, Ref. Number	Dose of VPA and Mode of Treatment	Type of Malformations	Comments
Bold et al. [102]	Mice, 100 to 600 mg subcutaneously on GD 6 to 10.	32% NTD and 100% spinal nerve malformations	VPA caused dose- and age-dependent malformations when different doses were administered.
Di Renzo et al. [103,119]	Mice, 400 mg single I.P. VPA on GD 8.	50% abnormal somite formation, very high rate of axial malformations, 11.6% exencephaly	One study is focused on the somitogenesis of VPA-exposed embryos within 24 h of treatment and the other showed that methionine pretreatment before VPA worsens the abnormal outcome.
Shafique & Winn, [104]	ICR Mice, 400 mg subcutaneously on GD 9.	37.89% NTD with 18% average exencephaly	Indicated the role of epigenetics in the mechanism of VPA-induced teratogenesis.
Tiboni et al. [105]	CD-1 Mice, 600 mg intraperitoneal on GD 8.	28% exencephaly, 76% axial skeletal defect and 23% lethality	Reported the possibility of sildenafil citrate in decreasing skeletal malformations but not exencephaly.
Binkerd et al. [113]	Sprague-Dawley rats. 200–800 mg orally from GD 8 to 17.	skeletal malformations, ventricular septal malformations and great vessel and urogenital malformations	Human teratogen VPA was accessed in a dose-dependent manner by treating each mouse with a single dose of 100, 200, 400, 600 or 800 mg on different gestational days.
Lin et al. [114]	Swiss Vancouver mice, single intraperitoneal injection of VPA 1.8 or 2.7 mmol/kg on GD 8.	11.1% external malformations, 40% visceral malformations, cleft palate, heart and kidney malformations	Reported four genes (Mtap2, Bmp8b, Stat3, and Heyl) as candidate target genes of VPA-induced malformations.
Elmazar, M.M.A. and H. Nau [120]	NMRI mice, single 300 mg or 400 mg on GD 8.	12.9% exencephaly, 20% lethality with VPA alone	The cases of exencephaly rise to 42.5% when VPA is co-administered with trimethoprim.