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

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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.