Dibutyl Phthalate Exposure Disrupts Evolutionarily Conserved Insulin and Glucagon-Like Signaling in Drosophila Males.
Phthalate diesters are commonly used as industrial plasticisers, as well as in cosmetics and skin care products, as a result people are constantly exposed to these xenobiotics. Recent epidemiological studies have found a correlation between circulating phthalate levels and type 2 diabetes, whereas animal studies indicate that phthalates are capable of disrupting endocrine signaling. Nonetheless, how phthalates interfere with metabolic function is still unclear. Here, we show that feeding Drosophila males the xenobiotic dibutyl phthalate (DBP) affects conserved insulin- and glucagon-like signaling. We report that raising flies on food containing DBP leads to starvation resistance, increased lipid storage, hyperglycemia, and hyperphagia. We go on to show that the starvation-resistance phenotype can be rescued by overexpression of the glucagon analogue adipokinetic hormone (Akh). Furthermore, although acute DBP exposure in adult flies is able to affect insulin levels, only chronic feeding influences Akh expression. We establish that raising flies on DBP-containing food or feeding adults DBP food affects the expression of homologous genes involved in xenobiotic and lipid metabolism (AHR [Drosophila ss], NR1I2 [Hr96], ABCB1 [MDR50], ABCC3 [MRP], and CYP3A4 [Cyp9f2]). Finally, we determined that the expression of these genes is also influenced by Akh. Our results provide comprehensive evidence that DBP can disrupt metabolism in Drosophila males, by regulating genes involved in glucose, lipid, and xenobiotic metabolism.
Functional Pharmacology, Department of Neuroscience, Uppsala University, 75124 Uppsala, Sweden.
Michael J
MJ
Williams
Functional Pharmacology, Department of Neuroscience, Uppsala University, 75124 Uppsala, Sweden.
Lyle
L
Wiemerslage
Functional Pharmacology, Department of Neuroscience, Uppsala University, 75124 Uppsala, Sweden.
Priya
P
Gohel
Functional Pharmacology, Department of Neuroscience, Uppsala University, 75124 Uppsala, Sweden.
Sania
S
Kheder
Functional Pharmacology, Department of Neuroscience, Uppsala University, 75124 Uppsala, Sweden.
Lakshmi V
LV
Kothegala
Functional Pharmacology, Department of Neuroscience, Uppsala University, 75124 Uppsala, Sweden.
Helgi B
HB
Schiöth
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003993:Dibutyl Phthalate / Q000633:toxicity*; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity; D005934:Glucagon / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D015398:Signal Transduction / Q000187:drug effects; D015262:Xenobiotics / Q000378:metabolism
D018435:ATP Binding Cassette Transporter, Subfamily B; D029721:Drosophila Proteins; D004785:Environmental Pollutants; D007328:Insulin; D015262:Xenobiotics; C083351:multidrug resistance protein 50, Drosophila; D003993:Dibutyl Phthalate; D005934:Glucagon; D051544:Cytochrome P-450 CYP3A