Abstract
Long chain alkylphenols are man-made compounds still present in industrial and agricultural processes. Their main use is domestic and they are widespread in household products, cleansers and cosmetics, leading to a global environmental and human contamination. These molecules are known to exert estrogen-like activities through binding to classical estrogen receptors. In vitro, they can also interact with the G-protein coupled estrogen receptor. Testicular germ cell tumor etiology and progression are proposed to be stimulated by lifelong estrogeno-mimetic exposure. We studied the transduction signaling pathways through which an alkyphenol mixture triggers testicular cancer cell proliferation in vitro and in vivo. Proliferation assays were monitored after exposure to a realistic mixture of 4-tert-octylphenol and 4-nonylphenol of either TCam-2 seminoma derived cells, NT2/D1 embryonal carcinoma cells or testis tumor in xenografted nude mice. Specific pharmacological inhibitors and gene-silencing strategies were used in TCam-2 cells in order to demonstrate that the alkylphenol mix triggers CREB-phosphorylation through a rapid, ERα36-PI3kinase non genomic pathway. Microarray analysis of the mixture target genes revealed that this pathway can modulate the expression of the DNA-methyltransferase-3 (Dnmt3) gene family which is involved in DNA methylation control. Our results highlight a key role for ERα36 in alkylphenol non genomic signaling in testicular germ cell tumors. Hence, ERα36-dependent control of the epigenetic status opens the way for the understanding of the link between endocrine disruptor exposure and the burden of hormone sensitive cancers.
Highlights
Over the last 50 years, the incidence of male reproductive disorders such as hypospadias, cryptorchidism, hypofertility and testis cancer has dramatically risen
A wide range of published data dealing with testicular germ cell tumor (TGCT) geographic incidence variation, epidemiological studies performed on migrant men, and exposure model analyses in vivo and in vitro strongly suggest the participation of endocrine disrupting compounds (EDCs) in both initiation and progression of testis cancer
To test if an alkylphenol mix such as M4 could act as a proliferation inducer in seminoma-derived (TCam-2) and embryonal carcinoma (NT2/D1) cell lines, the growth rate of TCam-2 and NT2/D1 cells was determined by counting the number of cells exposed to different concentrations of M4
Summary
Over the last 50 years, the incidence of male reproductive disorders such as hypospadias, cryptorchidism, hypofertility and testis cancer has dramatically risen. A wide range of published data dealing with TGCT geographic incidence variation, epidemiological studies performed on migrant men, and exposure model analyses in vivo and in vitro strongly suggest the participation of endocrine disrupting compounds (EDCs) in both initiation and progression of testis cancer. In occidentalized countries, this hypothesis emerge to explain the burden of testis cancer associated pathologies such as cryptorchidism, hypospadias, hypofertility, as well as increased incidence of other hormone sensitive cancer (breast, prostate, ovary, endometrium) [5,6,7,8]
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