Avobenzone suppresses proliferative activity of human trophoblast cells and induces apoptosis mediated by mitochondrial disruption
Introduction
Avobenzone (butyl methoxydibenzoylmethane) is an endocrine disruptor that directly binds to estrogen receptor β and acts as an estrogen agonist [[1], [2], [3]]. According to a survey in Switzerland, approximately 71% of personal care products contain avobenzone, which is the highest proportion among the various compositions [4]. The amount of avobenzone in personal care products is limited to 3% by The Food and Drug Administration (FDA) and 5% by Cosmetics Directive of the European Union, and it is toxic if products used frequently have concentrations of avobenzone greater than 5%. Avobenzone acts as an agonist or antagonist by reacting with various hormone receptors [5]. Additionally, avobenzone is found in underwater environments such as seawater swimming pools, making this potential toxin easily accessible to the human body [6]. In particular, under UV-irradiation and chlorination conditions, avobenzone produces a wide variety of eco-toxicant products which are much more reactive than avobenzone [7]. It is known to be toxic to aquatic organisms even at low concentrations [8]. Moreover, exposure of human immune cells to avobenzone promotes the release of inflammatory cytokines and reduces the viability of macrophages and monocytes at concentrations of 10 μg/mL (32 μM) [9]. However, little is known about the physiological activity of avobenzone in other types of human cells.
Human trophoblast cells form the placenta through a precisely controlled differentiation process during the early pregnancy of women. Routine exposure to various environmental factors is known to affect the viability, proliferation, and invasiveness of human trophoblast cells. The endocrine disruptor, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces apoptosis through mitochondrial dysfunction and reactive oxygen species (ROS) production in human trophoblast cells [10]. In addition, chemicals contained in personal care products and food additives such as propyl gallate, butyl paraben and decanoic acid can lead tomitochondrial defects and death of human trophoblast cells [[11], [12], [13]]. It is also known that pathways involving AKT or ERK1/2 signaling proteins are important for the survival and growth of human trophoblast cells, but it is unclear whether external environmental factors alter cell characteristics by modulating signal transduction pathways [14,15].
Therefore, the objectives of this study were to determine whether avobenzone affects the proliferation and death of human trophoblast HTR8/SVneo cells and whether AKT and ERK1/2 activities are regulated by avobenzone. We also measured mitochondrial membrane potential and mitochondrial Ca2+ concentration to analyze the effect of avobenzone on mitochondrial functions in HTR8/SVneo cells. Finally, we verified the expression of genes that may be targeted by avobenzone in HTR8/SVneo cells.
Section snippets
Chemicals
Avobenzone was purchased from Selleckchem (Houston, TX, USA). Antibodies against phosphorylated AKT (Ser473), P70S6 kinase (P70S6K, Thr421/Ser424), ribosomal protein 6 (S6, Ser235/Ser236), glycogen synthase kinase 3 beta (GSK3β, Ser9), and extracellular signal-regulated protein kinase 1 and 2 (ERK1/2, Thr202/Tyr204), and total AKT, P70S6K, S6, GSK3β, and ERK1/2 were purchased from Cell Signaling Technology (Beverly, MA, USA). LY294002 was purchased from Cell Signaling Technology and U0126 was
Avobenzone inhibits proliferative activities of human trophoblast cells
First, we performed a proliferation assay based on BrdU ELISA to determine whether avobenzone inhibits human trophoblast proliferation. HTR8/SVneo cells were treated with various concentrations (0, 1, 2, 5, 10, 20, and 50 μM) of avobenzone with 50 μM being the maximum concentration. A significant decrease in cell proliferation was observed at 5 μM (Fig. 1A). Avobenzone at 10 μM produced more than 50% inhibition of cell proliferation and 74.6% (P < 0.001) and 77.2% (P < 0.001) cell
Discussion
In present study, we found that avobenzone suppresses proliferation and induces apoptosis in human trophoblast cells. Moreover, avobenzone modulated the AKT and ERK1/2 signaling pathways. Furthermore, avobenzone induced depolarization of the mitochondrial membrane and elevated intracellular and mitochondrial Ca2+ concentrations in HTR8/SVneo cells as illustrated in Fig. 6. Finally, we found that avobenzone increased the expression of IFI27 and that expression of genes linked to enhancer to
Funding
This work was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI15C0810 awarded to G.S. and HI17C0929 awarded to W.L.).
Conflict of interest
The authors declare that there are no conflicts of interest.
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These authors contributed equally to this work.