Methylparaben induces cell-cycle arrest and caspase-3-mediated apoptosis in human placental BeWo cells

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ORIGINAL ARTICLE

Methylparaben induces cell‑cycle arrest and caspase‑3‑mediated apoptosis in human placental BeWo cells Ji‑Young Kim1 · Mi Jin Kim1 · Mi‑Jin An1 · Geun‑Seup Shin1 · Hyun‑Min Lee1 · Chul‑Hong Kim1 · Jung‑Woong Kim1  Accepted: 30 July 2020 © The Korean Society of Toxicogenomics and Toxicoproteomics 2020 2020

Abstract Background  Parabens are frequently used as antimicrobial preservatives in various commercials, pharmaceutical products, and foods. Recent studies have suggested that the exposure of pregnant women to methylparaben has adverse effects on the fetus. However, the biological mechanisms underlying the effects of methylparaben on human placental cells are yet to be elucidated. Objective  In this study, we determined that methylparaben induces cell death by affecting the growth, cell-cycle arrest, and apoptosis of human placental BeWo cells. We employed flow cytometry at the single-cell level for analyzing the expression of proteins related to cell cycle and apoptosis instead of using conventional methods. Results  The results demonstrated that treatment with methylparaben significantly decreased cell viability. We observed that methylparaben increased the protein level of cyclin B1, which arrested the cell cycle at sub-G1 status, and decreased the proportion of BeWo cells in the G2/M phase. We also observed that methylparaben induced caspase-3-mediated apoptosis in a time- and dose-dependent manner. Conclusion  These results suggested that methylparaben had cytotoxic adverse effects on human BeWo placenta cells through the induction of apoptosis and cell-cycle arrest. Keywords  Apoptosis · Methylparaben · Caspase-3 · Human placenta · BeWo cells

Introduction Parabens are alkyl esters of p-hydroxybenzoic acid, which are commonly used in a wide variety of commercial products including pharmaceuticals, cosmetics, and foods (Soni et al. 2005). The continued use of parabens increases exposure to humans via ingestion, inhalation, and dermal absorption (Smith et al. 2013; Janjua et al. 2008). Following exposure, parabens are extensively distributed in the body, and have been detected in urine, breast, and blood (Janjua et al. 2008; Barr et al. 2012; Ye et al. 2008). Although several reports have investigated the safety of parabens, the toxicological Electronic supplementary material  The online version of this article (https​://doi.org/10.1007/s1327​3-020-00097​-3) contains supplementary material, which is available to authorized users. * Jung‑Woong Kim [email protected] 1



Department of Life Science, Chung-Ang University, Seoul 06974, South Korea

properties of these esters have been the focus of concern since the 1990s (Darbre and Harvey 2008). Parabens act as xenoestrogens and disrupt hormone homeostasis in breast cancer MCF-7 cells (Okubo et al. 2001). In addition, paraben-induced cytotoxicity is related to the functional regulation of mitochondria and can lead to the death of hepatocytes (Nakagawa and Moore 1999). Parabens, particularly propylparaben, disturb the male reproductive system by