Spina bifida aperta induced by valproic acid and by all‐trans‐retinoic acid in the mouse: Distinct differences in morphology and periods of sensitivity

Abstract

The antiepileptic drug valproic acid (VPA) has been implicated as a human teratogen causing spina bifida aperta. Recently, we developed a mouse model inducing spina bifida aperta with VPA. To elucidate the pathogenesis of VPA-induced spina bifida aperta we now investigated the anatomy and histology of this defect in the mouse. The morphology of spina bifida aperta induced by all-trans-retinoic acid (RA) was used for comparison. Various doses of VPA and RA were administered at different times to determine the periods of sensitivity for inducing spina bifida aperta with these drugs. Each administration regimen consisted of three doses applied at intervals of 6 hr. RA induced spina bifida aperta during an earlier developmental period (day 8 of gestation) than VPA (day 9 of gestation). The most effective regimens for induction of spina bifida aperta in mice were injections of 3 x 500 mg VPA-Na/kg body weight (b.w.) intraperitoneally on day 9 of gestation at 0, 6, and 12 hr; RA (12.5 mg/kg b.w.) was given orally on day 8 of gestation at 12 and 18 hr, day 9 at 0 hr. VPA did not induce spina bifida aperta on day 8 of gestation and RA did not induce this effect on day 9 of gestation. Histological studies of day 18 fetuses carrying spina bifida aperta were performed. The spina bifida aperta induced by VPA shows a disorganized and necrotic spinal cord. In the vertebral canal were observed cell debris, blood cells, capillaries, macrophages, and rests of meninges. These results indicate that the spinal cord is almost destroyed at the affected section. In contrast, the spina bifida aperta induced by RA demonstrates a spinal cord organized in the gray and white matter, the dorsal and ventral horn. But the neural canal does not exist, only a layer of ependymal cells lies on the surface of the spinal cord. Our results indicate that the morphology of spina bifida aperta induced by VPA differed distinctly from that induced by RA in the mouse fetus. Moreover VPA produced a spina bifida aperta with a specific morphology. Also the period of sensitivity for induction of this lesion differed and occurred earlier for RA than for VPA. VPA and RA may possibly induce spina bifida aperta via different mechanisms in the mouse.

Ochratoxin A: The Continuing Enigma

“…These results were confirmed and determined to also hold true for rats and hamsters in subsequent studies carried out by the same group, with the most sensitive GD varying between 7 and 10, depending on species. 181−183 Similar observations of sensitivity windows have been made for other classical teratogens, that interfere with specific developmental processes, including valproic acid, 184 retinoic acid, 185 and thalidomide. 186 Hood and coworkers also reported an increased incidence of necrotic neuroectodermal cells in the brains and eyes of exposed mouse fetuses.…”

Cell motility is inhibited by the antiepileptic compound, valproic acid and its teratogenic analogues

“…The compound is a widely used antiepileptic drug. In 1988, one million patients were treated with it worldwide [Ehlers et al, 1992c]. Furthermore, it has been proven useful in the treatment of migraine [Jensen et al, 1994], bipolar disorder, and other psychiatric disorders [reviewed by Guay, 1995], and has been proposed as a chemotherapeutic drug in the treatment of cancer [Cinatl Jr. et al, 1996].…”

Prophylactic Effects of Melatonin on Sodium Valproate-Induced Neural Tube Defects and Skeletal Malformations in Rat Embryos

“…Administration of VPA on days 8-9 of gestation results in failure of cranial neural tube closure and spina bifida, as well as limb abnormalities such as syndactyly and oligodactyly (Ehlers et al, 1992). Menegola et al (1998) reported that the administration of 150-300 mg kg −1 sodium valproate subcutaneously to pregnant mice or rats every 8h during the first stages of somitogenesis is able to produce a very high incidence of malformations at the level of the axial skeleton.…”