Abstract
People are constantly exposed to phthalates, due to their common use in the production of plastics, pharmaceuticals, cosmetics and skin care products. The ability of phthalates to disrupt endocrine signaling, leading to developmental, reproductive and metabolic defects, has been studied, yet how phthalates interfere with these biological functions is still unclear. To uncover DBP interacting molecular pathways, we raised Drosophila melanogaster on food containing dibutyl phthalate (DBP) at various concentrations. Whole transcriptome analysis of adult Drosophila reveals that DBP exposure throughout development disrupts the expression of genes central to circadian rhythm regulation, including increased expression of vrille (vri, human NFIL3), timeless (tim, human TIMELESS) and period (per, human PER3), with decreased expression of Pigment-dispersing factor (Pdf). DBP exposure also alters the expression of the evolutionarily conserved nuclear receptor Hormone receptor-like in 38 (Hr38, human NR4A2), which is known to regulate Pdf expression. Furthermore, behavioral assays determined that exposing Drosophila to DBP throughout development modifies the circadian rhythm of adults. Although DBP inhibits the expression of signaling systems regulating vision, including Rh5 and Rh6, two light-sensing G-protein coupled receptors involved in the daily resetting of circadian rhythm, it does not influence eye development. Circadian rhythm genes are well conserved from flies to humans; therefore, we tested the effect of DBP exposure on human breast cells (MCF10A) and demonstrate that, similar to the fruit fly model, this exposure disrupts circadian rhythm (BMAL1 expression) at doses that promote the proliferation and migration ability of MCF10A cells. Our results are the first to provide comprehensive evidence that DBP interferes with circadian rhythm in both adult Drosophila and human cells, which may help to explain the broad physiological action of phthalates.
Highlights
Endocrine disrupting chemicals (EDCs), which include plasticizers, are prevalent in the environment and can induce severe deficits in reproduction, development, as well as provoke neural abnormalities (Colborn et al, 1993)
We found that dibutyl phthalate (DBP) exposure significantly increased Pigment dispersing factor (PDF) protein levels in the I-LNv neurons (Fig. 6), indicating that DBP exposure may influence the release of PDF peptides from these neurons
In order to find the appropriate concentrations for studying circadian rhythm, we looked at proliferation and migration because DBP is known to influence these phenotypes in human cancer cells (Chen and Chien, 2014; Saillenfait et al, 2008; Turner et al, 2013), we chose a concentration gradient (0.1 nM, 1 nM, 10 nM, 0.5 μM, 1 μM, 10 μM, 25 μM, 50 μM, 100 μM, 250 μM and 500 μM) to tested the cell proliferation ability, in order to get the most affective DBP concentration on MCF10A cells
Summary
Endocrine disrupting chemicals (EDCs), which include plasticizers, are prevalent in the environment and can induce severe deficits in reproduction, development, as well as provoke neural abnormalities (Colborn et al, 1993). The annual global production of one subfamily of plasticizers, the phthalates, is over 470 million pounds (Serrano et al, 2014). The use of dibutyl phthalate (DBP) has been widespread in the perfume, cosmetic, shampoo and medical device industries. Even though the use of DBP in cosmetic products has been forbidden in Europe since 2005, its persistence in the environment, including drinking water, means there is continued long-term human exposure through inhalation, oral, and dermal uptake (DominguezMorueco et al, 2014; Santana et al, 2014). Many epidemiological studies have associated circulating levels of phthalates and their metabolites with various health problems, including infertility and polycystic ovary syndrome (PCOS), precocious puberty, hormone dependent tumors, and several metabolic disorders (Huang et al, 2014; Kim and Park, 2014; Lind et al, 2012a; Lind et al, 2012b; Seidlova-Wuttke et al, 2005; Sun et al, 2014), none of these studies found a clear molecular link between phthalate exposure and these health risks
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