Reversal of prenatal heroin-induced alterations in hippocampal gene expression via transplantation of mesenchymal stem cells during adulthood.

Neurobehavioral teratology is the study of typically subtle neurobehavioral birth defects. Our previously described mouse model demonstrated septohippocampal cholinergic innervation-related molecular and behavioral deficits after prenatal exposure to heroin. Since the alterations are below malformation level, they are likely to represent consequences of regulatory processes, feasibly gene expression. Consequently, in the present study pregnant mice were injected with heroin on gestation days 9-18 and were transplanted with mesenchymal stem cells (MSC) on postnatal day (PD) 105. The hippocampi of the offspring were analyzed on PD120 for the expression of the pertinent genes. Heroin induced global gender-dependent statistically significant changes in the expression of several genes. Significant Treatment X Sex interaction occurred in D1 and SOX2 genes (p < 0.01). Transplantation of MSC reversed the prenatal heroin-induced alterations in approximately 80% of the genes. The reversal index (RI), shifting the score of the heroin-exposed offspring by transplantation back toward the control level, was 0.61 ± 0.10 for the difference from RI = 0 (p < 0.001), confirming the validity of the effect of the neuroteratogens across variations among different genes. The present study suggests that neurobehavioral defects induced by prenatal heroin exposure are likely to be a consequence of regulatory changes. This study on prenatal exposure to insults with subsequent MSC therapy provides a model for elucidating the mechanisms of both the neuroteratogenicity and the therapy, steps that are critical for progress toward therapeutic applications.