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Dibutyl phthalate exposure disrupts conserved circadian rhythm signaling systems in Drosophila
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
Visa övriga samt affilieringar
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Due to their common use as industrial plasticizers, agents in cosmetics and inclusion in skin care products, people are constantly exposed to phthalate xenobiotics. Although much research has focused on their ability to disrupt endocrine signaling, leading to developmental, reproductive and metabolic defects, how phthalates interfere with these biological functions is still unclear. Using whole transcriptome analysis, we demonstrate that exposing the genetically-tractable model system Drosophila melanogaster to the xenobiotic Dibutyl Pthalate (DBP) throughout development interferes with neuronal systems associated with vision and circadian rhythm. Of note, while DBP did not influence with eye development, it inhibited the expression of signaling systems regulating vision, including Rhodopsin 5 (Rh5) and Rhodopsin 6 (Rh6), two light-sensing G-protein coupled receptors involved in the daily resetting of circadian rhythm. Furthermore, DBP influenced the expression of genes central to circadian rhythm regulation, including vrille (vri, human NFIL3), timeless (tim, human TIMELESS), period (per, human PER3) and Pigment-dispersing factor (Pdf). Finally, we demonstrate that DBP disrupts circadian rhythm by interacting with the evolutionarily conserved nuclear receptor Hormone receptor-like in 38 (Hr38, human NR4A2), which in turn regulates Pdf expression. Our results are the first to provide comprehensive evidence that DBP interferes with the circadian rhythm system.

Nationell ämneskategori
Neurovetenskaper Biokemi och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:uu:diva-356541OAI: oai:DiVA.org:uu-356541DiVA, id: diva2:1236099
Tillgänglig från: 2018-07-31 Skapad: 2018-07-31 Senast uppdaterad: 2018-07-31
Ingår i avhandling
1. Exposure to xenobiotic chemicals disrupts metabolism, rhythmicity and cell proliferation in Drosophila melanogaster
Öppna denna publikation i ny flik eller fönster >>Exposure to xenobiotic chemicals disrupts metabolism, rhythmicity and cell proliferation in Drosophila melanogaster
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 50
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1481
Nyckelord
xenobiotics, metabolism, insulin signalling, circadian rhythm, carcinogen
Nationell ämneskategori
Neurovetenskaper Biokemi och molekylärbiologi Farmakologi och toxikologi
Forskningsämne
Biomedicinsk laboratorievetenskap
Identifikatorer
urn:nbn:se:uu:diva-356545 (URN)978-91-513-0391-8 (ISBN)
Disputation
2018-09-21, B22, BMC, Husargatan 3, Uppsala, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-08-24 Skapad: 2018-07-31 Senast uppdaterad: 2018-09-07

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