Valentine Suteau1, Claire Briet2, Maÿlis Lebeault3, Louis Gourdin4, Daniel Henrion5, Patrice Rodien6, Mathilde Munier7. 1. UMR CNRS 6015, INSERM 1083, MITOVASC Institute, 3 rue Roger Amsler, 49000 Angers, France; Department of Endocrinology, University Hospital, 4 rue Larrey, 49933 Angers, France. Electronic address: Valentine.Courant@chu-angers.fr. 2. UMR CNRS 6015, INSERM 1083, MITOVASC Institute, 3 rue Roger Amsler, 49000 Angers, France; Department of Endocrinology, University Hospital, 4 rue Larrey, 49933 Angers, France; Reference Center for Rare Diseases of Thyroid and Hormone Receptors, University Hospital, 4 rue Larrey, 49933 Angers, France. Electronic address: claire.briet@chu-angers.fr. 3. UMR CNRS 6015, INSERM 1083, MITOVASC Institute, 3 rue Roger Amsler, 49000 Angers, France; Department of Endocrinology, University Hospital, 4 rue Larrey, 49933 Angers, France. Electronic address: MaylisLebeault@chu-angers.fr. 4. UMR CNRS 6015, INSERM 1083, MITOVASC Institute, 3 rue Roger Amsler, 49000 Angers, France; Reference Center for Rare Diseases of Thyroid and Hormone Receptors, University Hospital, 4 rue Larrey, 49933 Angers, France. Electronic address: gourdin.louis@gmail.com. 5. UMR CNRS 6015, INSERM 1083, MITOVASC Institute, 3 rue Roger Amsler, 49000 Angers, France. Electronic address: daniel.henrion@univ-angers.fr. 6. UMR CNRS 6015, INSERM 1083, MITOVASC Institute, 3 rue Roger Amsler, 49000 Angers, France; Department of Endocrinology, University Hospital, 4 rue Larrey, 49933 Angers, France; Reference Center for Rare Diseases of Thyroid and Hormone Receptors, University Hospital, 4 rue Larrey, 49933 Angers, France. Electronic address: PaRodien@chu-angers.fr. 7. UMR CNRS 6015, INSERM 1083, MITOVASC Institute, 3 rue Roger Amsler, 49000 Angers, France; Department of Endocrinology, University Hospital, 4 rue Larrey, 49933 Angers, France; Reference Center for Rare Diseases of Thyroid and Hormone Receptors, University Hospital, 4 rue Larrey, 49933 Angers, France. Electronic address: mathilde.munier@univ-angers.fr.
Abstract
BACKGROUND: The presence of chemical pollutants in the environment can affect human health. Epidemiological and in vivo experimental studies reveal reprotoxic effects (undescended testis) of phthalates (diethylhexyl phthalate (DEHP), dibutyl phthalate (DBP)) and bisphenol A (BPA), resulting in particular of a decrease in INSL3 (Insulin-Like 3 peptide) production. This hormone is essential for normal testis development and acts on a G protein-coupled receptor: RXFP2. OBJECTIVES: The aim of this study was to evaluate the individual and combined impacts of DEHP, DBP, and BPA on human RXFP2 (hRXFP2) activity. METHODS: We used HEK293 cells transiently transfected with hRXFP2 and receptor activity was analyzed by measuring intracellular cAMP production. The mixture was established at concentrations reported in human amniotic fluid, for the three compounds. RESULTS: Individually, DEHP, DBP and BPA increased the response to INSL3 by 19.3 to 27.5%. This potentiating effect was specific for RXFP2, because it was absent in the cells which did not express this receptor. On the other hand, and interestingly, the mixture of the three compounds reduced significantly the response to INSL3 by 12%, and the observed effects were opposite to those predicted, suggesting an antagonist effect. DISCUSSION- CONCLUSION: Taken together, our results demonstrate for the first time that a mixture of phthalates and BPA present in human amniotic fluid disturbs the human RXFP2 function. Moreover, we demonstrate that mixture can produce potential antagonistic effects that are not displayed by the compounds, individually.
BACKGROUND: The presence of chemical pollutants in the environment can affect human health. Epidemiological and in vivo experimental studies reveal reprotoxic effects (undescended testis) of phthalates (diethylhexyl phthalate (DEHP), dibutyl phthalate (DBP)) and bisphenol A (BPA), resulting in particular of a decrease in INSL3 (Insulin-Like 3 peptide) production. This hormone is essential for normal testis development and acts on a G protein-coupled receptor: RXFP2. OBJECTIVES: The aim of this study was to evaluate the individual and combined impacts of DEHP, DBP, and BPA on human RXFP2 (hRXFP2) activity. METHODS: We used HEK293 cells transiently transfected with hRXFP2 and receptor activity was analyzed by measuring intracellular cAMP production. The mixture was established at concentrations reported in human amniotic fluid, for the three compounds. RESULTS: Individually, DEHP, DBP and BPA increased the response to INSL3 by 19.3 to 27.5%. This potentiating effect was specific for RXFP2, because it was absent in the cells which did not express this receptor. On the other hand, and interestingly, the mixture of the three compounds reduced significantly the response to INSL3 by 12%, and the observed effects were opposite to those predicted, suggesting an antagonist effect. DISCUSSION- CONCLUSION: Taken together, our results demonstrate for the first time that a mixture of phthalates and BPA present in human amniotic fluid disturbs the human RXFP2 function. Moreover, we demonstrate that mixture can produce potential antagonistic effects that are not displayed by the compounds, individually.