Persistent endocrine-disrupting chemicals found in human follicular fluid stimulate IGF1 secretion by adult ovarian granulosa cell tumor spheroids and thereby increase proliferation of non-cancer ovarian granulosa cells

Abstract

Insulin-like growth factor-1 (IGF1) is a hormone involved in cell proliferation. We previously showed that IGF1 directly stimulates cell proliferation in granulosa cell tumors (GCTs). Estrogen regulates IGF1 expression in several reproductive organs including the uterus and ovaries. This study aimed to investigate the effects of a mixture of endocrine-disrupting chemicals (EDCs) on secretion of IGF1 by COV434 and KGN cells, which have been used as in vitro models of juvenile and adult GCTs, respectively. The EDC mixture contained perfluorooctanoate, perfluorooctane sulfonate, 2,2-dichlorodiphenyldichloroethylene, hexachlorobenzene, and polychlorinated biphenyl 153, which are persistent hormonally active environmental toxicants present in ovarian follicular fluid (FF). Expression and secretion of IGF1 were significantly higher in GTCs than in HGrC1 human non-cancer granulosa cells (with the profile HGrC1 < COV434 < KGN). Treatment with the EDC mixture as well as individual test compounds significantly increased IGF1 secretion in KGN cells. Moreover, IGFBP3 gene expression in KGN cells was downregulated after treatment with the EDC mixtures. The estrogen receptor alpha pathway was involved in this effect. Conditioned medium of KGN cells treated with the EDC mixture increased proliferation of HGrC1 human non-cancer granulosa cells. These results indicate that the mixture of EDCs found in FF increases secretion of IGF1 by KGN cells and thus indirectly contributes to progression of adult GCTs, and increases proliferation of non-cancer granulosa cells.