Phthalates are ubiquitous environmental pollutants found in plastic and PVC-containing devices. Human exposure to phthalates poses a serious risk to testicular function. Hallmarks of phthalate induced testicular injury include disruption of Sertoli-germ cell adhesion and FSH-stimulated cAMP accumulation by Sertoli cells. Although the mechanism of phthalate induced testicular injury is not known, these data suggest that both G protein-coupled receptor signaling and cell-cell adhesion are early targets of phthalate injury.Flamingo proteins contain extracellular cadherin cell-cell adhesion domains coupled to seven transmembrane helices, thus indicating their involvement in both cell-cell adhesion and G protein mediated signal transduction. Three Flamingo homologs are expressed in rat testis at the mRNA level, and their expression pattern is affected by phthalate exposure. The mRNA expression of Flamingo 1 and 2 decreased to 70% of control 3 hours post exposure and continued to decline at later time points. This grant proposal investigates the mechanism of phthalate induced testicular injury by examining this hypothesis: Phthalates induce phosphorylation, internalization and degradation of Flamingo 1 and 2 protein leading to Sertoli-germ cell detachment and germ cell apoptosis.
