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Developmental bisphenol A diglycidyl ether (BADGE) exposure causes cell over-proliferation in Drosophila
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Since the estrogenic activity of bisphenol A had been reported, the industry started to find a proper replacement. Bisphenol A diglycidyl ether (BADGE) is one of the derivatives of BPA which is used widely in epoxy resin manufactory. Recently, some studies have demonstrated the adverse effects of BADGE on reproduction and development. However, the knowledge of BADGE is still scarce. Because of its hydrolytic property, BADGE is usually detected at a low level in commodities and the influences seem to be underestimated. In our study, we use the whole transcriptome sequencing to assess the effects of developmental BADGE exposure on Drosophila melanogaster. Notably, the genes related to cell proliferation are significantly affected by BADGE exposure. More detailed, a group of mitotic genes, including string (stg, human CDC25A), Cyclin B (CycB, human CCNB1), Cyclin E (CycE, human CCNE1), and pan gu (png, human NEK11), are detectable overexpressed. Phenotypically, we observe that BADGE induces severe hemocytes over-proliferation in the 3rd instar larvae, but does not cause morphological damage of the larval lymph gland and blood circulation. In conclusion, we provide evidence to show the carcinogenic potential of BADGE and raise the concern of better understanding of xenobiotics. 

National Category
Biochemistry and Molecular Biology Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-356544OAI: oai:DiVA.org:uu-356544DiVA, id: diva2:1236100
Available from: 2018-07-31 Created: 2018-07-31 Last updated: 2018-07-31
In thesis
1. Exposure to xenobiotic chemicals disrupts metabolism, rhythmicity and cell proliferation in Drosophila melanogaster
Open this publication in new window or tab >>Exposure to xenobiotic chemicals disrupts metabolism, rhythmicity and cell proliferation in Drosophila melanogaster
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 50
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1481
Keywords
xenobiotics, metabolism, insulin signalling, circadian rhythm, carcinogen
National Category
Neurosciences Biochemistry and Molecular Biology Pharmacology and Toxicology
Research subject
Biomedical Laboratory Science
Identifiers
urn:nbn:se:uu:diva-356545 (URN)978-91-513-0391-8 (ISBN)
Public defence
2018-09-21, B22, BMC, Husargatan 3, Uppsala, 13:00 (English)
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Supervisors
Available from: 2018-08-24 Created: 2018-07-31 Last updated: 2018-09-07

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Cao, HaoWilliams, Michael J.Schiöth, Helgi B.

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