Butyl paraben promotes apoptosis in human trophoblast cells
through increased oxidative stress-induced endoplasmic
Fuller W. Bazer
Department of Biotechnology and Institute
of Animal Molecular Biotechnology, College
of Life Sciences and Biotechnology, Korea
University, Seoul 02841, Republic of Korea
Department of Biomedical Sciences,
Catholic Kwandong University, Gangneung
25601, Republic of Korea
Department of Animal Science and Center
for Animal Biotechnology and Genomics,
Texas A&M University, College Station,
Gwonhwa Song, Department of
Biotechnology, College of Life Sciences and
Biotechnology, Korea University, Seoul,
02841, Republic of Korea.
Korea Health Technology R&D Project
through the Korea Health Industry
Development Institute (KHIDI), the Ministry
of Health & Welfare, Republic of Korea,
Grant/Award Number: HI15C0810 and
Butyl paraben (BP) has antimicrobial effects and is widely used as a preservative in cosmetics,
foods, and pharmaceuticals. It is also absorbed into various tissues of the human body. It is known
that BP is measurable in maternal and fetal tissues during pregnancy, but the effects of BP on pla-
cental development, essential for maintaining normal pregnancy, are unclear. Therefore, we
investigated the effect of BP on the proliferation, apoptosis, and invasiveness of human tropho-
blast cells, using an HTR8/SVneo cell line. BP inhibited cell proliferation and induced both
apoptosis and endoplasmic reticulum stress. In addition, BP promoted the production of intracellu-
lar reactive oxygen species, increased Ca
concentration in HTR8/SVneo cells, and induced
mitochondrial membrane depolarization. BP also inhibited the activation of PI3K/AKT pathways
including AKT, ribosomal protein S6, P70 S6 kinase, and glycogen synthase kinase 3b.Further-
more, pretreatment of cells with LY294002 (an AKT inhibitor) and U0126 (ERK1/2 inhibitor)
revealed that ERK1/2 activity is also involved in BP-mediated signal transduction in HTR8/SVneo
cells. We therefore suggest that exposing human trophoblast cells to BP diminishes normal physio-
logical activity, leading to apoptosis and problems with early placental development.
Butyl paraben, trophoblast, ROS, ER stress
Parabens are alkyl ester compounds of parahydroxybenzoic acid, and
are widely used as preservatives in cosmetics, foods, beverages, and
pharmaceuticals. Parabens exert potent antimicrobial effects through
the inhibition of ATPases and phosphotransferases, and through dis-
ruption of the membrane transport system.
Parabens are mainly syn-
thesized industrially and are known to disrupt endocrine function by
mimicking the active form of natural estrogens.
Butyl paraben (BP) is
more estrogenic than other parabens, including methyl, ethyl, and
BP contained in consumer products has been thought
to be safe; however, toxicity studies regarding BP are increasing, as it is
easily absorbed and retained in body tissues, including the skin and gas-
BP causes adverse effects, particularly in the
development and function of the reproductive organs. Various animal
studies revealed that exposure to BP changes histological characteris-
tics of the uterus and hinders steroidogenesis.
exposure to BP is related to adverse reproductive outcomes, although
the mechanism by which maternal exposure to BP affects normal preg-
nancy maintenance is unclear.
Normal placental development is essential for maintenance of
pregnancy as it ensures the supply of adequate nutrients to the fetus.
Precise regulation of trophoblast differentiation and growth is impor-
tant in trophoblast invasion of the maternal endometrium, where these
cells modify blood flow dynamics by inducing spiral artery remodeling.
Failure of vascular remodeling due to incomplete trophoblast invasion
causes pregnancy disorders, such as preeclampsia and intrauterine
Various external factors, including diet and envi-
ronmental pollutants, affect the survival and invasiveness of human
trophoblast cells. Typically, bisphenol A (BPA) inhibits the invasion of
Changwon Yang and Whasun Lim authors contributed equally to this study.
2018 Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/tox Environmental Toxicology. 2018;33:436–445.
Received: 22 October 2017
Revised: 26 December 2017
Accepted: 27 December 2017