An Alkylphenol Mix Promotes Seminoma Derived Cell Proliferation through an ERalpha36-Mediated Mechanism

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.

Origine développementale et environnementale de l’infertilité masculine

“…L'exposition néonatale au bisphénol A (BPA) induit, quant à elle, une hyperméthylation du promoteur des gènes codant les récepteurs des oestrogènes dans le testicule adulte qui est directement liée à une augmentation des taux d'ADN méthyltransférases 3a et 3b [25]. Les méthyltransférases semblent être un élément critique dans les méca-nismes d'action des perturbateurs endocriniens puisque des défauts de leur expression sont également retrouvés dans d'autres modèles, tels que celui de souris exposées en période périnatale à du di-2-(éthylhexyl) phtalate [26] ou bien aux alkylphénols [27]. In vitro, les alkylphénols inhibent l'expression de la DNMT3 dans des lignées de cancer testiculaire, DNMT3 étant connue pour contrôler la méthyla-tion du promoteur des récepteurs des oestrogènes [27].…”

“…Les méthyltransférases semblent être un élément critique dans les méca-nismes d'action des perturbateurs endocriniens puisque des défauts de leur expression sont également retrouvés dans d'autres modèles, tels que celui de souris exposées en période périnatale à du di-2-(éthylhexyl) phtalate [26] ou bien aux alkylphénols [27]. In vitro, les alkylphénols inhibent l'expression de la DNMT3 dans des lignées de cancer testiculaire, DNMT3 étant connue pour contrôler la méthyla-tion du promoteur des récepteurs des oestrogènes [27]. Ces défauts de méthylation pourraient faire le lien entre exposition aux perturbateurs endocriniens oestrogéniques et cancers testiculaires.…”

Gender and Age Related Modulation of Xenoestrogen-Induced Tumorigenesis

“…As we already discussed, altere transplacental programming is the critical step. However, xenoestrogen exposure during puberty (with its dramatic endocrine changes) may also play a role in the multi-step process of testicular carcinogenesis; alkylphenols (detergent by-products able to act as ER-agonists) do trigger a rapid, ERα36-PI3kinase pathway, which, in its turn, can modulate the expression of the DNAmethyltransferase-3 (Dnmt3) gene family which is involved in DNA methylation control, a mechanism suggested to play a role in testicular cancer [86]. It is noteworthy that, when investigating dietary risk factors, testicular cancer was significantly related with transplacental (maternal) and prepubertal consumption of cheese [87].…”

Gender and Age Related Modulation of Xenoestrogen-Induced Tumorigenesis

“…As we already discussed, altere transplacental programming is the critical step. However, xenoestrogen exposure during puberty (with its dramatic endocrine changes) may also play a role in the multi-step process of testicular carcinogenesis; alkylphenols (detergent by-products able to act as ER-agonists) do trigger a rapid, ERα36-PI3kinase pathway, which, in its turn, can modulate the expression of the DNA-methyltransferase-3 (Dnmt3) gene family which is involved in DNA methylation control, a mechanism suggested to play a role in testicular cancer [86]. It is noteworthy that, when investigating dietary risk factors, testicular cancer was significantly related with transplacental (maternal) and prepubertal consumption of cheese [87].…”