***** seminarMLから情報転載 *****



日時:平成21年11月18日(水) 14:00-16:00
場所:国立医薬品食品衛生研究所 講堂(最寄り駅:東急田園都市線 桜新町駅)

講演者:Dr. Richard E. Peterson
    School of Pharmacy and Molecular and Environmental Toxicology Center&s_comma;
    University of Wisconsin&s_comma; Madison&s_comma; WI&s_comma; USA

演題:Dioxin&s_comma; AHR Signaling and Impaired Prostate Development

Treatment of C57BL/6J mouse dams with
2&s_comma;3&s_comma;7&s_comma;8-tetrachlorodibenzo-p-dioxin (TCDD) interferes with mouse
prostate morphogenesis by impairing prostatic bud formation in the
fetal urogenital sinus (UGS). TCDD completely inhibits prostatic bud
formation in the ventral UGS region&s_comma; causing ventral prostate
agenesis&s_comma; and decreases the number of buds formed in the dorsal UGS
region&s_comma; thereby reducing dorsolateral prostate size. TCDD-induced
down-regulation of sox9b is known to play a critical role in the
mechanism by which it inhibits zebrafish fin regeneration and jaw
development (Mathew et al.&s_comma; 2008 and Xiong et al.&s_comma; 2008). Here we
report that TCDD-induced down-regulation of β-catenin-dependent SOX9
plays a pivotal role in the mechanism by which it inhibits mouse
prostate development. In control male mice&s_comma; β-catenin-mediated
transcription is localized to UGS basal epithelial cells that are
involved in prostatic bud formation. TCDD exposure (5 μg/kg&s_comma;
maternal dose) on embryonic day (E) 15.5 activates aryl-hydrocarbon
receptor-responsive gene expression in these cells and reduces
abundance of SOX9 and other β-catenin regulated proteins on E16.5.
Targeted β-catenin deletion in UGS basal epithelial cells produces a
UGS phenotype strikingly similar to that induced by TCDD&s_comma; which
includes reduced SOX9 expression and impaired prostatic bud
formation. Expression of a dominant stable β-catenin in UGS
epithelium protects against TCDD-induced prostatic bud inhibition in
vivo and in cultured UGS tissues. Ectopic activation of SOX9 also
protects against TCDD-induced prostatic bud inhibition in UGS organ
culture. Taken together&s_comma; these results suggest that TCDD disrupts β
-catenin signaling to repress SOX9&s_comma; a transcription factor known to
be required for ventral prostatic bud formation (Thomsen et al.&s_comma;
2008). Down-regulation of SOX9 in UGS basal epithelium may be the
mechanism by which TCDD disrupts prostatic bud formation in C57BL/6J mice.


環境衛生化学部 第3室長
TEL&FAX 03-3700-9346
E-mail nsugimot@nihs.go.jp