title: Mono-(2-ethylhexyl)-phthalate (MEHP) affects ERK-dependent GDNF signalling in mouse stem-progenitor spermatogonia.
abstract: Many commercial and household products such as lubricants, cosmetics, plastics, and paint contain phthalates, in particular bis-(2-ethyhexyl)-phthalate (DEHP). As a consequence, phthalates have been found in a number of locations and foods (streambeds, household dust, bottled water and dairy products). Epidemiological and animal studies analysing phthalate exposure in males provide evidence of degradation in sperm quality, associated to an increase in the incidence of genital birth defects and testicular cancers. In the testis, spermatogenesis is maintained throughout life by a small number of spermatogonial stem cells (SSCs) that self-renew or differentiate to produce adequate numbers of spermatozoa. Disruption or alteration of SSC self-renewal induce decreased sperm count and sperm quality, or may potentially lead to testicular cancer. GDNF, or glial cell-line-derived neurotrophic factor, is a growth factor that is essential for the self-renewal of SSCs and continuous spermatogenesis. In the present study, the SSC-derived cell line C18-4 was used as a model for preliminary assessment of the effects of mono-(2-ethylhexyl)-phthalate (MEHP, main metabolite of DEHP) on spermatogonial stem cells. Our data demonstrate that MEHP disrupts one of the known GDNF signalling pathways in these cells. MEHP induced a decrease of C18-4 cell viability in a time- and dose-dependent manner, as well as a disruption of ERK1/2 activation but not of SRC signalling. As a result, we observed a decrease of expression of the transcription factor FOS, which is downstream of the GDNF/ERK1/2 axis in these cells. Taken together, our data suggest that MEHP exposure affects SSC proliferation through inhibition of specific signalling molecules.
authors.affiliation: Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, 2001 South Lincoln Avenue, Urbana, IL 61802, USA.
authors.forename: Benjamin E G
authors.initials: BE
authors.lastname: Lucas
authors.forename: Christopher
authors.initials: C
authors.lastname: Fields
authors.forename: Neeraj
authors.initials: N
authors.lastname: Joshi
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Hofmann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives* / Q000633:toxicity; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013093:Spermatogonia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D017382:Reactive Oxygen Species; D004051:Diethylhexyl Phthalate; D048049:Extracellular Signal-Regulated MAP Kinases; C016599:mono-(2-ethylhexyl)phthalate