In utero exposure to dioxin causes neocortical dysgenesis through the actions of p27Kip1.
Dioxins have been reported to exert various adverse effects, including cell-cycle dysregulation in vitro and impairment of spatial learning and memory after in utero exposure in rodents. Furthermore, children born to mothers who are exposed to dioxin analogs polychlorinated dibenzofurans or polychlorinated biphenyls have developmental impairments in cognitive functions. Here, we show that in utero exposure to dioxins in mice alters differentiation patterns of neural progenitors and leads to decreased numbers of non-GABAergic neurons and thinner deep neocortical layers. This reduction in number of non-GABAergic neurons is assumed to be caused by accumulation of cyclin-dependent kinase inhibitor p27(Kip1) in nuclei of neural progenitors. Lending support to this presumption, mice lacking p27(Kip1) are not susceptible to in utero dioxin exposure. These results show that environmental pollutants may affect neocortical histogenesis through alterations of functions of specific gene(s)/protein(s) (in our case, dioxins), exerting adverse effects by altering functions of p27(Kip1).
Mitsuhashi
Takayuki
T
Department of Pediatrics, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan. ttakahashi@z3.keio.jp
Yonemoto
Junzo
J
Sone
Hideko
H
Kosuge
Yasuhiro
Y
Kosaki
Kenjiro
K
Takahashi
Takao
T
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000002:abnormalities / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D018811:Maternal Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D014599:Uterus / Q000187:drug effects*
C493961:Cdkn1b protein, mouse; D000072317:Polychlorinated Dibenzodioxins; D050760:Cyclin-Dependent Kinase Inhibitor p27
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