Butylated hydroxytoluene induces dysregulation of calcium homeostasis and endoplasmic reticulum stress resulting in mouse Leydig cell death

Jiyeon Ham, Whasun Lim, Kwang Youn Whang, Gwonhwa Song

Research output: Contribution to journalArticle

Abstract

Butylated hydroxytoluene (BHT) is a synthetic phenolic antioxidant that has been used as an additive for fat- or oil-containing foods. The exposure index value increases with extended usage of the chemical. Further, estimated total amount of BHT could exceed standard regulation, considering dietary intake or another exposure. Although BHT may induce side effects in reproductive systems, adequate research had not yet been performed to confirm them. In this study, we investigated the effects of BHT on mouse Leydig cells (TM3), which are components of testis. Our results indicated that BHT suppressed cellular proliferation and induced cell cycle arrest in TM3 cells. Moreover, BHT hampered cytosolic and mitochondrial calcium homeostasis in TM3 cells. Furthermore, BHT treatment led to endoplasmic reticulum (ER) stress and DNA fragmentation, simultaneously stimulating intrinsic apoptosis signal transduction. To elucidate the mode of action of BHT on Leydig cells, we performed western blot analysis and confirmed the activation of the PI3K/AKT and MAPK pathways. Collectively, our results demonstrated that BHT has toxic effects on mouse Leydig cells via induction of calcium dysregulation and ER-mitochondria dysfunction.

Original languageEnglish
Article number113421
JournalEnvironmental Pollution
Volume256
DOIs
Publication statusPublished - 2020 Jan

Fingerprint

Butylated Hydroxytoluene
Endoplasmic Reticulum Stress
Leydig Cells
Cell death
Calcium
Homeostasis
Cell Death
Signal transduction
Mitochondria
Oils and fats
Antioxidants
DNA
Chemical activation
Cells
Activation Analysis
Poisons
DNA Fragmentation
Cell Cycle Checkpoints
Phosphatidylinositol 3-Kinases
Endoplasmic Reticulum

Keywords

  • BHT
  • Calcium homeostasis
  • ER stress
  • Leydig cell

ASJC Scopus subject areas

  • Toxicology
  • Pollution
  • Health, Toxicology and Mutagenesis

Cite this

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title = "Butylated hydroxytoluene induces dysregulation of calcium homeostasis and endoplasmic reticulum stress resulting in mouse Leydig cell death",
abstract = "Butylated hydroxytoluene (BHT) is a synthetic phenolic antioxidant that has been used as an additive for fat- or oil-containing foods. The exposure index value increases with extended usage of the chemical. Further, estimated total amount of BHT could exceed standard regulation, considering dietary intake or another exposure. Although BHT may induce side effects in reproductive systems, adequate research had not yet been performed to confirm them. In this study, we investigated the effects of BHT on mouse Leydig cells (TM3), which are components of testis. Our results indicated that BHT suppressed cellular proliferation and induced cell cycle arrest in TM3 cells. Moreover, BHT hampered cytosolic and mitochondrial calcium homeostasis in TM3 cells. Furthermore, BHT treatment led to endoplasmic reticulum (ER) stress and DNA fragmentation, simultaneously stimulating intrinsic apoptosis signal transduction. To elucidate the mode of action of BHT on Leydig cells, we performed western blot analysis and confirmed the activation of the PI3K/AKT and MAPK pathways. Collectively, our results demonstrated that BHT has toxic effects on mouse Leydig cells via induction of calcium dysregulation and ER-mitochondria dysfunction.",
keywords = "BHT, Calcium homeostasis, ER stress, Leydig cell",
author = "Jiyeon Ham and Whasun Lim and Whang, {Kwang Youn} and Gwonhwa Song",
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AU - Ham, Jiyeon

AU - Lim, Whasun

AU - Whang, Kwang Youn

AU - Song, Gwonhwa

PY - 2020/1

Y1 - 2020/1

N2 - Butylated hydroxytoluene (BHT) is a synthetic phenolic antioxidant that has been used as an additive for fat- or oil-containing foods. The exposure index value increases with extended usage of the chemical. Further, estimated total amount of BHT could exceed standard regulation, considering dietary intake or another exposure. Although BHT may induce side effects in reproductive systems, adequate research had not yet been performed to confirm them. In this study, we investigated the effects of BHT on mouse Leydig cells (TM3), which are components of testis. Our results indicated that BHT suppressed cellular proliferation and induced cell cycle arrest in TM3 cells. Moreover, BHT hampered cytosolic and mitochondrial calcium homeostasis in TM3 cells. Furthermore, BHT treatment led to endoplasmic reticulum (ER) stress and DNA fragmentation, simultaneously stimulating intrinsic apoptosis signal transduction. To elucidate the mode of action of BHT on Leydig cells, we performed western blot analysis and confirmed the activation of the PI3K/AKT and MAPK pathways. Collectively, our results demonstrated that BHT has toxic effects on mouse Leydig cells via induction of calcium dysregulation and ER-mitochondria dysfunction.

AB - Butylated hydroxytoluene (BHT) is a synthetic phenolic antioxidant that has been used as an additive for fat- or oil-containing foods. The exposure index value increases with extended usage of the chemical. Further, estimated total amount of BHT could exceed standard regulation, considering dietary intake or another exposure. Although BHT may induce side effects in reproductive systems, adequate research had not yet been performed to confirm them. In this study, we investigated the effects of BHT on mouse Leydig cells (TM3), which are components of testis. Our results indicated that BHT suppressed cellular proliferation and induced cell cycle arrest in TM3 cells. Moreover, BHT hampered cytosolic and mitochondrial calcium homeostasis in TM3 cells. Furthermore, BHT treatment led to endoplasmic reticulum (ER) stress and DNA fragmentation, simultaneously stimulating intrinsic apoptosis signal transduction. To elucidate the mode of action of BHT on Leydig cells, we performed western blot analysis and confirmed the activation of the PI3K/AKT and MAPK pathways. Collectively, our results demonstrated that BHT has toxic effects on mouse Leydig cells via induction of calcium dysregulation and ER-mitochondria dysfunction.

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