Testicular germ cell cancer is the most frequent cancer of the young men with an increasing incidence all over the world. Pathogenesis and reasons of this increase remain unknown but epidemiological and clinical data have suggested that like genital malformations and sperm impairment, it could include developmental and environmental factors, including fetal exposure to environmental endocrine disruptors (EEDs). Several groups including ours have shown that TGCC is estrogen dependent especially seminoma the most frequent histological type. By studying in vitro human seminoma cell lines, it was possible to identify two different kind of effects of estrogens and xenoestrogens through at least two different estrogen receptors. Estradiol (pM and nM) and diethylstilbestrol induced a suppressive genomic effect by binding to ERβ, the only classical nuclear receptor expressed in normal and malignant germ cells. However, estradiol, estradiol linked to bovine serum albumin (E2-BSA) which does not cross the membrane, bisphenol A and atrazine, induced a proliferative effect through the non classical membrane G protein related estrogen receptor GPER/GPR30, by a rapid non genomic activation of transduction pathways including several G protein-dependent kinases. Bisphenol A acted at very low doses (pM and nM) similar to the concentrations which were found in human male cord blood, illustrating a very high affinity for GPR30 explaining the paradoxal inverse U shaped dose response curve. GPR30 was found to be overexpressed in seminomas partly due to the presence of a particular genetic polymorphism and ERβ was decreased when compared with normal testicular tissue possibly linked to epigenetic modifications which can be induced in rodent by fetal exposure to EEDs. Carcinogenetic effect of EEDs by impairing germ stem cells development is supported by TGCC estrogen dependency. However, more longitudinal prospective epidemiological studies and molecular epigenetic screening are necessary to clearly demonstrate this developmental relationship.
18 - 21 May 2019
European Society of Endocrinology