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(American Journal of Pathology. 2007;170:667-679.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060339

Gestational Vitamin B Deficiency Leads to Homocysteine-Associated Brain Apoptosis and Alters Neurobehavioral Development in Rats

Sébastien A. Blaise*, Emmanuelle Nédélec*, Henri Schroeder{dagger}, Jean-Marc Alberto*, Carine Bossenmeyer-Pourié*, Jean-Louis Guéant* and Jean-Luc Daval*

From Unité 724,* Institut National de la Santé et de la Recherché Médicale, Faculté de Médecine, Vandoeuvre-lès-Nancy; and Neurosciences Comportementales,{dagger} Institut National de la Recherché Agronomique, Faculté des Sciences, Vandoeuvre-lés-Nancy, France

Hyperhomocysteinemia has been identified as a risk factor for neurological disorders. To study the influence of early deficiency in nutritional determinants of hyperhomocysteinemia on the developing rat brain, dams were fed a standard diet or a diet lacking methyl groups during gestation and lactation. Homocysteinemia progressively increased in the offspring of the deficient group and at 21 days reached 13.3 ± 3.7 µmol/L versus 6.8 ± 0.3 µmol/L in controls. Homocysteine accumulated in both neurons and astrocytes of selective brain structures including the hippocampus, the cerebellum, the striatum, and the neurogenic subventricular zone. Most homocysteine-positive cells expressed p53 and displayed fragmented DNA indicative of apoptosis. Righting reflex and negative geotaxis revealed a delay in the onset of integration capacities in the deficient group. Between 19 and 21 days, a poorer success score was recorded in deficient animals in a locomotor coordination test. A switch to normal food after weaning allowed restoration of normal homocysteinemia. Nevertheless, at 80 days of age, the exploratory behavior in the elevated-plus maze and the learning and memory behavior in the eight-arm maze revealed that early vitamin B deprivation is associated with persistent functional disabilities, possibly resulting from the ensuing neurotoxic effects of homocysteine.




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