PMID- 31470217 OWN - NLM STAT- MEDLINE DCOM- 20200225 LR - 20200225 IS - 1873-6750 (Electronic) IS - 0160-4120 (Linking) VI - 132 DP - 2019 Nov TI - Human blood-based exposure levels of persistent organic pollutant (POP) mixtures antagonise androgen receptor transactivation and translocation. PG - 105083 LID - S0160-4120(19)30761-5 [pii] LID - 10.1016/j.envint.2019.105083 [doi] AB - INTRODUCTION: Human exposure to persistent organic pollutants (POPs) has been linked to genitourinary health-related conditions such as decreased sperm quality, hypospadias, and prostate cancer (PCa). Conventional risk assessment of POPs focuses on individual compounds. However, in real life, individuals are exposed to many compounds simultaneously. This might lead to combinatorial effects whereby the global effect of the mixture is different from the effect of the single elements or subgroups. POP mixtures may act as endocrine disruptors via the androgen receptor (AR) and potentially contribute to PCa development. AIM: To determine the endocrine disrupting activity of a POP mixture and sub-mixtures based upon exposure levels detected in a human Scandinavian population, on AR transactivation and translocation in vitro. MATERIALS AND METHODS: The Total POP mixture combined 29 chemicals modelled on the exposure profile of a Scandinavian population and 6 sub-mixtures: brominated (Br), chlorinated (Cl), Cl + Br, perfluorinated (PFAA), PFAA + Br, PFAA + Cl, ranging from 1/10x to 500x relative to what is found in human blood. Transactivation was measured by reporter gene assay (RGA) and translocation activity was measured by high content analysis (HCA), each using stably transfected AR model cell lines. RESULTS: No agonist activity in terms of transactivation and translocation was detected for any POP mixtures. In the presence of testosterone the Cl + Br mixture at 100x and 500x blood level antagonised AR transactivation, whereas the PFAA mixture at blood level increased AR transactivation (P < 0.05). In the presence of testosterone the Cl and PFAA + Br mixtures at 1/10x, 1x, and 50x blood level antagonised AR translocation (P < 0.05). CONCLUSION: Taken together, some combinations of POP mixtures can interfere with AR translocation. However, in the transactivation assay, these combinations did not affect gene transactivation. Other POP combinations were identified here as modulators of AR-induced gene transactivation without affecting AR translocation. Thus, to fully evaluate the effect of environmental toxins on AR signalling, both types of assays need to be applied. CI - Copyright (c) 2019 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - McComb, J AU - McComb J AD - Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast BT9 5DL, Northern Ireland, United Kingdom. FAU - Mills, I G AU - Mills IG AD - Prostate Cancer UK/Movember Centre of Excellence, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry, and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, Northern Ireland, United Kingdom; Nuffield Department of Surgical Sciences, University of Oxford, Level 6, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, United Kingdom. FAU - Muller, M AU - Muller M AD - Laboratory for Organogenesis and Regeneration, GIGA-Research, University of Liege, Liege 4000, Belgium. FAU - Berntsen, H F AU - Berntsen HF AD - Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Post-box 369 sentrum, 0102 Oslo, Norway; Department of Administration, Lab Animal Unit, National Institute of Occupational Health, P.O. Box 5330, Oslo, Norway. FAU - Zimmer, K E AU - Zimmer KE AD - Department of Basic Sciences and Aquatic Medicine, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Post-box 369 sentrum, 0102 Oslo, Norway. FAU - Ropstad, E AU - Ropstad E AD - Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Post-box 369 sentrum, 0102 Oslo, Norway. FAU - Verhaegen, S AU - Verhaegen S AD - Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Post-box 369 sentrum, 0102 Oslo, Norway. FAU - Connolly, L AU - Connolly L AD - Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast BT9 5DL, Northern Ireland, United Kingdom. Electronic address: l.connolly@qub.ac.uk. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190827 PL - Netherlands TA - Environ Int JT - Environment international JID - 7807270 RN - 0 (AR protein, human) RN - 0 (Androgen Receptor Antagonists) RN - 0 (Endocrine Disruptors) RN - 0 (Environmental Pollutants) RN - 0 (Receptors, Androgen) RN - 3XMK78S47O (Testosterone) SB - IM MH - Androgen Receptor Antagonists/*blood/toxicity MH - Cells, Cultured MH - Endocrine Disruptors/*blood/toxicity MH - Environmental Pollutants/*blood/*toxicity MH - Genes, Reporter MH - Humans MH - *Receptors, Androgen MH - Testosterone/pharmacology MH - Transcriptional Activation/*drug effects MH - Translocation, Genetic/drug effects OTO - NOTNLM OT - Androgen receptor OT - Cocktail effect OT - Endocrine disrupting chemical OT - High content screening OT - Mixture OT - Persistent organic pollutant EDAT- 2019/08/31 06:00 MHDA- 2020/02/26 06:00 CRDT- 2019/08/31 06:00 PHST- 2019/04/04 00:00 [received] PHST- 2019/08/01 00:00 [revised] PHST- 2019/08/02 00:00 [accepted] PHST- 2019/08/31 06:00 [pubmed] PHST- 2020/02/26 06:00 [medline] PHST- 2019/08/31 06:00 [entrez] AID - S0160-4120(19)30761-5 [pii] AID - 10.1016/j.envint.2019.105083 [doi] PST - ppublish SO - Environ Int. 2019 Nov;132:105083. doi: 10.1016/j.envint.2019.105083. Epub 2019 Aug 27.