Stimulatory effects of combined endocrine disruptors on MA-10 Leydig cell steroid production and lipid homeostasis
| Autor: | Toshihide Kobayashi, Peter Greimel, Steven Jones, Annie Boisvert, Françoise Hullin-Matsuda, Andrada Naghi, Martine Culty, Vassilios Papadopoulos |
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| Přispěvatelé: | Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty endocrine system [SDV]Life Sciences [q-bio] Genistein 010501 environmental sciences Endocrine Disruptors Toxicology 01 natural sciences Polymerase Chain Reaction 03 medical and health sciences chemistry.chemical_compound Mice Internal medicine Cell Line Tumor Diethylhexyl Phthalate medicine Animals Homeostasis Liver X receptor Phospholipids Progesterone 0105 earth and related environmental sciences Leydig cell biology Dose-Response Relationship Drug Phthalate Leydig Cells Lipid metabolism Lipid Metabolism 3. Good health 030104 developmental biology medicine.anatomical_structure Endocrinology chemistry Endocrine disruptor HMG-CoA reductase biology.protein Steroids Chromatography Thin Layer Transcription Factors |
| Zdroj: | Toxicology Toxicology, 2016, 355-356, pp.21-30. ⟨10.1016/j.tox.2016.05.008⟩ |
| Popis: | International audience; Previous work in our laboratory demonstrated that in-utero exposure to a mixture of the phytoestrogen Genistein (GEN), and plasticizer DEHP, induces short- and long-term alterations in testicular gene and protein expression different from individual exposures. These studies identified fetal and adult Leydig cells as sensitive targets for low dose endocrine disruptor (ED) mixtures. To further investigate the direct effects and mechanisms of toxicity of GEN and DEHP, MA-10 mouse tumor Leydig cells were exposed in-vitro to varying concentrations of GEN and MEHP, the principal bioactive metabolite of DEHP. Combined 10muM GEN+10muM MEHP had a stimulatory effect on basal progesterone production. Consistent with increased androgenicity, the mRNA of steroidogenic and cholesterol mediators Star, Cyp11a, Srb1 and Hsl, as well as upstream orphan nuclear receptors Nr2f2 and Sf1 were all significantly increased uniquely in the mixture treatment group. Insl3, a sensitive marker of Leydig endocrine disruption and cell function, was significantly decreased by combined GEN+MEHP. Lipid analysis by high-performance thin layer chromatography demonstrated the ability of combined 10muM combined GEN+MEHP, but not individual exposures, to increase levels of several neutral lipids and phospholipid classes, indicating a generalized deregulation of lipid homeostasis. Further investigation by qPCR analysis revealed a concomitant increase in cholesterol (Hmgcoa) and phospholipid (Srebp1c, Fasn) mediator mRNAs, suggesting the possible involvement of upstream LXRalpha agonism. These results suggest a deregulation of MA-10 Leydig function in response to a combination of GEN+MEHP. We propose a working model for GEN+MEHP doses relevant to human exposure involving LXR agonism and activation of other transcription factors. Taken more broadly, this research highlights the importance of assessing the impact of ED mixtures in multiple toxicological models across a range of environmentally relevant doses. |
| Databáze: | OpenAIRE |
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