Toxic effects of in utero exposure to dioxins on cerebral histogenesis: quantitative analysis using mathematical model of cerebral histogenesis.

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2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental pollutant known to disturb hormonal homeostasis as well as more fundamental cell proliferative behavior. Among the recognized specific effects upon histogenesis due to exposure to TCDD in utero are impairment of development of immune and urogenital systems in mice and impairment of thyroid function. With respect to cellular proliferative behavior, TCDD inhibits G1 phase progression by inducing p27Kip1 expression in a hepatoma cell line and in fetal thymocytesis In rodents exposure to TCDD in utero may be associated with impaired spatial learning and memory. The cell biological basis for this impairment and its consequences for CNS histogenesis are unknown. Because cell cycle kinetics is critically controlled at the G1 restriction point by the action of p27Kip1, we consider that TCDD exposure may act upon this regulatory mechanism, at least in part, to disturb cerebral histogenesis.We have investigated the conseque … More nce of TCDD exposure in utero on embryonic day (E) 7 upon cerebral histogenesis, by examining the cytoarchitecture of the postnatal day 21 brain and developing cerebral wall and cell cycle kinetics of the PVE at E12.MethodWe exposed C57BL/6N mice fetus with TCDD by oral gavage (20 μg/kg body weight) at E7. We analyzed 1.mRNA expression level and subcellular localization pattern of cell cycle regulatory genes, 2.length of each phase of cell cycle, 3.probability of differentiation (Q) in neuronal progenitor cells (NPC) at E12. Additionally, we measured 1.size of telencephalon, 2.thickness of cortices, 3.numbers and densities of GABA-positive, negative neurons and glial cells, respectively, in layer specific manner at P21 mice.ResultIn utero exposure to TCDD resulted in 1.increase in p27Kip1 protein level in nuclei, 2.increase in length of G1 phase of cell cycle, 3.increase in Q in NPC at E12. TCDD-exposed P21 telencephalon showed decrease in length, width, and cortical thickness. This cortical thinning was mainly due to decrease in number of non-GABAergic projection neurons in layer V-VIDiscussionTCDD exposure in utero resulted in abnormal cortical histogenesis (decreased thickness of neocortex). We speculate that TCDD exposure increased p27Kip1 protein in nuclei of NPC that lead to increase in both G1 phase and Q. Thus premature increase in Q decrease the total output of projection neurons in the neocotex by decreasing the maximum number of NPC in the course of neuronogenesis. We speculate that decrease in number of projection neurons in layer V-VI in TCDD exposed mice might be resulted from premature switch of neuronal fate from deep layer to superficial neuronal phenotype by abnormal increase in Q fraction by TCDD exposure. Less