IN UTERO EXPOSURE TO DIOXIN CAUSES NEOCORTICAL DYSGENESIS

Objectives: TCDD, most potent dioxin, is an environmental pollutant known to disturb hormonal homeostasis and induce maldevelopment of immune and urogenital systems in mice. In CNS, in utero and lactational exposures to TCDD affect spatial learning and memory in rats. TCDD is also known to alter cell cycle kinetics by inducing cell cycle regulatory gene p27Kip1 in a hepatoma cell line and in fetal thymocytes. We have previously shown that G1 phase regulation of neural progenitor cells (NPC) plays a critical role in cerebral histogenesis. We also showed that TCDD exposure in utero affect cell cycle kinetics of NPCs on embryonic day 14 (E14). Taken together, we hypothesized that TCDD exposure may perturb proliferation of NPC of the developing brain and hence disturb neocortical histogenesis.

Methods: We exposed pregnant mice with TCDD on E7 and investigated cell cycle kinetics of NPC on E12 and cytoarchitecture of mature neocortex.

Results: We found that 1) decreased thickness of mature neocortex due to reduced number of neurons in deep cortical layers, 2) abnormal accumulation of p27Kip1 protein in nuclei of NPC and 3) increased probability of cell cycle exit (Q).

Conclusion: We concluded that nuclear accumulation of p27Kip1 by TCDD is the major molecular mechanism by which Q increased prematurely. As Q of a given cell cycle and the layer destination of neurons arising from that cell cycle are closely correlated, premature increase in Q would result in premature switch of neuronal phenotype from deep to superficial layers. As a consequence, total number of projection neurons would be reduced in deep cortical layers.