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Drosophila Melanogaster Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1481 Exposure to xenobiotic chemicals disrupts metabolism, rhythmicity and cell proliferation in Drosophila melanogaster HAO CAO ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-513-0391-8 UPPSALA urn:nbn:se:uu:diva-356545 2018 Dissertation presented at Uppsala University to be publicly examined in B22, BMC, Husargatan 3, Uppsala, Friday, 21 September 2018 at 13:00 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Faculty examiner: Professor Jan Larsson (Umeå University, Department of Molecular Biology). Abstract Cao, H. 2018. Exposure to xenobiotic chemicals disrupts metabolism, rhythmicity and cell proliferation in Drosophila melanogaster. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1481. 50 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0391-8. Most species are constantly exposed to xenobiotic chemicals through multiple routes. Among all categories of xenobiotics, phthalates and bisphenols are two of the most widely used plasticizers and can be found in polyvinyl chloride (PVC) materials, medical devices and even drinking water. In paper I, we found that bis-(2-ethylhexyl) phthalate (DEHP) exposure caused a significant decrease in circulating carbohydrates and insulin-related genes. The Multidrug- Resistance like Protein 1 (MRP1, MRP in Drosophila) belongs to the ATP-binding cassette transporter family, and previous studies revealed the importance of MRP1 for transporting xenobiotics. However, the function of MRP1 in metabolism and other biological processes is still unclear. Therefore, in paper II, we showed that knocking down MRP expression in Malpighian tubules, the physiological equivalence of the vertebrate kidney, led to disrupted lipid homeostasis and oxidative resistance. In paper III and IV, we initially used whole transcriptome sequencing to assess the genetic interferences of exposure to Dibutyl Phthalate (DBP) and Bisphenol A Diglycidyl Ether (BADGE). The reproductive and developmental disruptions of DBP had been reported in many studies. However, the mechanism is still unclear. In paper III, we observed that DBP interfered with neuronal systems associated circadian genes, including in vrille (vri, human NFIL3), timeless (tim, human TIMELESS), period (per, human PER3) and Pigment-dispersing factor (Pdf). Furthermore, we demonstrated that the evolutionarily conserved gene, Hormone receptor-like in 38 (Hr38, human NR4A2) was involved in responding to DBP and regulated Pdf expression as a consequence. In paper IV, BADGE, a BPA-substitute, was tested for its disruptive effects on Drosophila. Based on the transcriptome sequencing, we found that several mitotic genes, including string (stg, human CDC25A), Cyclin B (CycB, human CCNB1), Cyclin E (CycE, human CCNE1), and pan gu (png, human NEK11), had detectable overexpression by BADGE exposure. Developmental exposure to BADGE induced a large increase of hemocytes in fly 3rd instar larvae, while it did not damage the morphological structure of lymph gland and blood circulation. To summarize, our studies describe the potential disruptions of the industrial xenobiotics and provide the mechanistic hints for future investigations. Keywords: xenobiotics, metabolism, insulin signalling, circadian rhythm, carcinogen Hao Cao, Department of Neuroscience, Functional Pharmacology, Box 593, Uppsala University, SE-75124 Uppsala, Sweden. © Hao Cao 2018 ISSN 1651-6206 ISBN 978-91-513-0391-8 urn:nbn:se:uu:diva-356545 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-356545) To my family and friends. List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Cao H, Wiemerslage L, Marttila PS, Williams MJ, Schiöth HB, Bis-(2-ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster. Basic Clin Pharma- col Toxicol. 2016 Sep;119(3):309-16. II Cao H, Kimari M, Maronitis G, Williams MJ, Schiöth HB, Multidrug-Resistance like Protein 1 activity in Malpighian tu- bules regulates lipid homeostasis in Drosophila. Manuscript. III Cao H, Hosseini K, Siyahtiri MM, Maestri G, Shirazi M, Wil- liams MJ, Schiöth HB, Dibutyl phthalate exposure disrupts con- served circadian rhythm signaling systems in Drosophila. Man- uscript. IV Cao H, Lindkvist T, Mothes TJ, Williams MJ, Schiöth HB, Developmental bisphenol A diglycidyl ether (BADGE) expo- sure causes cell over-proliferation in Drosophila. Manuscript. Reprints were made with permission from the respective publishers. Additional publications • Zheleznyakova GY, Cao H, Schiöth HB, BDNF DNA methylation changes as a biomarker of psychiatric disorders: literature review and open access database analysis. Behav Brain Funct. 2016 Jun 6;12(1):17. • Wiemerslage L, Islam R, van der Kamp C, Cao H, Olivo G, Ence- Eriksson F, Castillo S, Larsen AL, Bandstein M, Dahlberg LS, Perland E, Gustavsson V, Nilsson J, Vogel H, Schurmann A, Larsson EM, Rask-Andersen M, Benedict C, Schiöth HB, A DNA methyla- tion site within the KLF13 gene is associated with orexigenic pro- cesses based on neural responses and ghrelin levels. Int J Obes (Lond). 2017 Jun;41(6):990-994. Contents Introduction ................................................................................................... 11 Drosophila melanogaster in fundamental research .................................. 12 Conserved metabolic system ............................................................... 12 Tools in Drosophila research ............................................................... 13 Circadian rhythm and activity in Drosophila ........................................... 13 Endocrine Disruptors (EDCs) and Phthalates .......................................... 15 Bis-(2-ethylhexyl) Phthalate (DEHP) .................................................. 15 Di-butyl Phthalate (DBP) .................................................................... 16 BPA alternatives and Bisphenol A diglycidyl ether (BADGE) ............... 16 Non-monotonic dose-response curve (NMDRC) ..................................... 16 Xenobiotic metabolism and ABC transporters ......................................... 17 Aims .............................................................................................................. 19 Materials and methods .................................................................................. 20 Fly strains, maintenance, and toxin feeding pattern ................................. 20 Fly strains ............................................................................................ 20 Fly maintenance ................................................................................... 20 Toxin feeding pattern ........................................................................... 20 Library preparation, sequencing, and data analysis.................................. 21 Biochemical and molecular assays ........................................................... 22 RNA extraction and cDNA synthesis .................................................. 22 qRT-PCR ............................................................................................. 22 Carbohydrate assay .............................................................................. 23 Lipid measurement .............................................................................. 23 TAG assay ........................................................................................... 24 ROS detection ...................................................................................... 24 Larvae bleeding and hemocytes quantification ................................... 24 Confocal imaging ................................................................................ 25 Behavioral assays ..................................................................................... 25 Starvation assay ................................................................................... 25 Paraquat resistance............................................................................... 25 Circadian rhythm assay ........................................................................ 26 FlyPAD ................................................................................................ 26 Statistical analysis .................................................................................... 27 Results ........................................................................................................... 28 Paper I ...................................................................................................... 28 Paper II ..................................................................................................... 29 Paper III .................................................................................................... 30 Paper IV ................................................................................................... 33 Conclusions and discussions ......................................................................... 35 Perspectives .................................................................................................. 38 Acknowledgements ....................................................................................... 39 References ..................................................................................................... 40 Appendix I- list of
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