estis after 2 and 7 days of DEHP treat ment, suggesting also a deregulation of cell adhesion molecules in seminiferous tubules. DEHP decreases the response to external factors, such as the Vascular Endothelial Growth Factor or the Epidermal Growth Factor through under expression of neuropilin 2 and sorting nexin 6 respectively. Nrp2 is a mem brane receptor capable of binding VEGF and sema phorins, therefore its under expression may inhibit cell adhesion and migration via the loss of integrins. Snx6 is able to interact with EGF receptor and Trans forming Growth Factor b receptor. Under expression of snx6 and thbs1 may lead to decreased interaction with Latent TGF Binding Protein in the upstream of the TGF b pathway contributing to the repression of the TGF b signaling pathway.
Under expression of TGF b is known to decrease apoptosis in rodent hepatocytes treated with peroxi some proliferators. Organelle transport and cytoskeleton remodelling DEHP also interferes with functions of microtubules. Kif23, which encodes a kinesin protein, was highly over expressed after 5 hrs and 24 hrs of DEHP exposure. Kif23 has been shown Drug_discovery to transport membranous organelles and protein com plexes from cell nucleus to cell periphery in a microtu bule and ATP dependent manner. Doublecortin like kinase is a microtubule associated protein encod ing a Ca2 calmodulin dependent kinase. Its activities on binding and microtubule polymerization facilitate cell motility by remodelling the microtubule cytoskele ton. Over expression of dclk at 24 hrs of DEHP treatment is in line with an increased trend in b tubulin.
Calmoduline like 3 was over expressed after 24 hrs of DEHP exposure. Calmodulin is a cal cium binding protein that translates the Ca2 signal into a wide variety of cellular processes, including the regula tion of cytoskeleton remodelling acting with Caldesmon or with Wnt pathway. Calml3 is a CaM family member protein which increases cell motility by stabiliz ing and increasing myosin 10 for cell migration. Other genes involved in signal transduction pathways and cytoskeleton regulation We measured an over expression level of phosphatidyli nositol 3 kinase r1 using Differential Display and qPCR. Pi3k is a key signalling molecule in the PIP3 signalling transduction pathway and in actin reorganiza tion and cell adhesion and is able to regulate the synthesis of collagen I.
An activation of PI3K is also associated with a phosphorylation dependent activation of Akt which contributes to tumorigenesis and metasta sis. The over expression of pi3kr1 can be related to the under expression of ctnnbip1 which interacts with b catenin. In addition to the function of b catenin in the actin cytoskeleton, its role in the regulation of Akt pathway activation or in Wnt pathway regulation is advanced. This protein forms part of a complex that captures growth and proliferation signals from the cell surface and is then activated to stimulate the expression of genes involved in cell prolifera