TY - JOUR
T1 - Butylated Hydroxyanisole Exerts Neurotoxic Effects by Promoting Cytosolic Calcium Accumulation and Endoplasmic Reticulum Stress in Astrocytes
AU - Park, Sunwoo
AU - Lee, Jin Young
AU - Lim, Whasun
AU - You, Seungkwon
AU - Song, Gwonhwa
N1 - Funding Information:
This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare (Grant HI17C0929) and the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and Information and Communications Technology (ICT) (MSIT) (2018R1C1B6009048).
Funding Information:
This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare (Grant HI17C0929) and the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and Information and Communications Technology (ICT) (MSIT) (2018R1C1B6009048).
Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/8/28
Y1 - 2019/8/28
N2 - Astrocytes provide nutritional support, regulate inflammation, and perform synaptic functions in the human brain. Although butylated hydroxyanisole (BHA) is a well-known antioxidant, several studies in animals have indicated BHA-mediated liver toxicity, retardation in reproductive organ development and learning, and sleep deficit. However, the specific effects of BHA on human astrocytes and the underlying mechanisms are yet unclear. Here, we investigated the antigrowth effects of BHA through cell cycle arrest and downregulation of regulatory protein expression. The typical cell proliferative signaling pathways, phosphoinositide 3-kinase/protein kinase B and extracellular signal-regulated kinase 1/2, were downregulated in astrocytes after BHA treatment. BHA increased the levels of pro-apoptotic proteins, such as BAX, cytochrome c, cleaved caspase 3, and cleaved caspase 9, and decreased the level of anti-apoptotic protein BCL-XL. It also increased the cytosolic calcium level and the expression of endoplasmic reticulum stress proteins. Treatment with BAPTA-AM, a calcium chelator, attenuated the increased levels of ER stress proteins and cleaved members of the caspase family. We further performed an in vivo evaluation of the neurotoxic effect of BHA on zebrafish embryos and glial fibrillary acidic protein, a representative astrocyte biomarker, in a gfap:eGFP zebrafish transgenic model. Our results provide clear evidence of the potent cytotoxic effects of BHA on human astrocytes, which lead to disruption of the brain and nerve development.
AB - Astrocytes provide nutritional support, regulate inflammation, and perform synaptic functions in the human brain. Although butylated hydroxyanisole (BHA) is a well-known antioxidant, several studies in animals have indicated BHA-mediated liver toxicity, retardation in reproductive organ development and learning, and sleep deficit. However, the specific effects of BHA on human astrocytes and the underlying mechanisms are yet unclear. Here, we investigated the antigrowth effects of BHA through cell cycle arrest and downregulation of regulatory protein expression. The typical cell proliferative signaling pathways, phosphoinositide 3-kinase/protein kinase B and extracellular signal-regulated kinase 1/2, were downregulated in astrocytes after BHA treatment. BHA increased the levels of pro-apoptotic proteins, such as BAX, cytochrome c, cleaved caspase 3, and cleaved caspase 9, and decreased the level of anti-apoptotic protein BCL-XL. It also increased the cytosolic calcium level and the expression of endoplasmic reticulum stress proteins. Treatment with BAPTA-AM, a calcium chelator, attenuated the increased levels of ER stress proteins and cleaved members of the caspase family. We further performed an in vivo evaluation of the neurotoxic effect of BHA on zebrafish embryos and glial fibrillary acidic protein, a representative astrocyte biomarker, in a gfap:eGFP zebrafish transgenic model. Our results provide clear evidence of the potent cytotoxic effects of BHA on human astrocytes, which lead to disruption of the brain and nerve development.
KW - astrocytes
KW - brain development
KW - butylated hydroxyanisole
KW - calcium imbalance
KW - zebrafish
UR - http://www.scopus.com/inward/record.url?scp=85071639237&partnerID=8YFLogxK
U2 - 10.1021/acs.jafc.9b02899
DO - 10.1021/acs.jafc.9b02899
M3 - Article
C2 - 31381342
AN - SCOPUS:85071639237
SN - 0021-8561
VL - 67
SP - 9618
EP - 9629
JO - Journal of Agricultural and Food Chemistry
JF - Journal of Agricultural and Food Chemistry
IS - 34
ER -