Clinical and experimental studies have suggested that estrogens, the archetype of female hormones, participate in the control of male germ cell proliferation and that fetal exposure to environmental estrogens may contribute to hypofertility and/or to testicular germ cell cancer (TGCT). However the underlying mechanisms remain to be elucidated.

Estradiol 17 conjugated to bovine serum albumin (E2-BSA), was able to stimulate human testicular seminoma cell proliferation by triggering a rapid, non genomic, membrane-mediated activation of Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) and Cyclic-AMP-dependent protein kinase A (PKA). Both ERK1/2 and PKA participated to this promoting effect. This activation was associated with phosphorylation of the transcription factor CREB (Cyclic AMP Response Element Binding protein) and the nuclear factor Rb (Retinoblastoma protein). Enhanced proliferation together with ERK activation could be reversed by pertussis toxin, a G protein inhibitor. Estrogen receptors (ERs) in JKT-1 were characterized by Immunofluorescence, subcellular fractioning, and Western blot. JKT-1 cells did not express ER but ER which localized to the mitochondria and the nucleus but not to the membrane. Moreover neither ICI182780, a classical ER antagonist or tamoxifen, a selective estrogen receptor modulator, could reverse E2-BSA induced promoting effect.

Estrogens contribute to human testicular germ cell cancer proliferation by rapid activation of ERK1/2 and PKA through a membrane non classical estrogen receptor. This non genomic effect represents a new basis for understanding the estrogenic control of spermatogenesis and evaluating the role of fetal exposure to xenoestrogens during malignant transformation of testicular germ stem cells.