Interrelation between dioxin, protein phosphorylation and tissue specific expression and function of the SF1 and MIS gene

类固醇生成因子1(SF1)对肾上腺和性腺的发育和性别分化是必不可少的。它是几种荷尔蒙的主要转录调节因子。Mis(苗勒氏抑制物质)和类固醇合成酶基因，在生殖过程中对下丘脑-垂体-性腺轴的功能至关重要。最近发现，接触2，3，7，8-四氯二苯并-对-二恶英(Dioxin)和相关接触物最敏感地与人类生殖系统的障碍有关。二恶英的毒性作用大部分(如果不是全部)是由芳香烃受体(AhR)介导的，该受体与二恶英结合后与芳香烃核转运体二聚化。本研究的目的是要弄清：(1)二恶英是否通过影响USF1/2或SOX9结合来干扰SF1基因的表达；(2)二恶英调节的AhR以一种二恶英调控的方式(通过其LxxLL基序)与SF1或其伴侣SOX9、WT1、GATA4或DAX1相互作用，从而干扰MIS的表达；(4)这些事件受到PKA介导的磷酸化的影响。我们预计，这些研究将为人类生殖相关基因的失调提供洞察力，从而发现二恶英毒性的新方面，这显然是公共卫生利益的问题。

The steroidogenic factor 1 (SF1) is essential for adrenal and gonadal development and sexual differentiation. It is a primary transcriptional regulator of several hormones eg. MIS (Müllerian inhibitory substance) and steroidogenic enzyme genes, critical for the function of the hypothalamic-piuitary-gonadal axis in reproduction. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and related contminants has recently been discovered to most sensitively be associated with disturbances in the human reproductive system. Most if not all of dioxins toxic effects are mediated by the aryl hydrocarbon receptor (AhR), wich upon dioxin binding dimerizes with the aryl hydrocarbon nuclear translocator. The objective of the proposed project is to find out whether: (1) dioxin interferes with the expression of the SF1 gene by affecting USF1/2 or SOX9 binding, (2) AhR in a dioxin-modulated fashion interacts (via its LXXLL motifs) which SF1 or with its partners SOX9, WT1, GATA4 or DAX1 and thus interferes with expression of MIS, (4) these events are influenced by PKA-mediated phosphorylation. We envision that these studies will provide insights into the disregulation of genes involved in human reproduction and thus uncover new aspects of dioxin toxicity, which is of obvious public health interest.