Butylated hydroxyanisole induces testicular dysfunction in mouse testis cells by dysregulating calcium homeostasis and stimulating endoplasmic reticulum stress

Jiyeon Ham; Whasun Lim; Seungkwon You; Gwonhwa Song

doi:10.1016/j.scitotenv.2019.134775

Butylated hydroxyanisole induces testicular dysfunction in mouse testis cells by dysregulating calcium homeostasis and stimulating endoplasmic reticulum stress

Jiyeon Ham, Whasun Lim, Seungkwon You, Gwonhwa Song

Department of Biotechnology

Research output: Contribution to journal › Article › peer-review

35 Citations (Scopus)

Abstract

Butylated hydroxyanisole (BHA), a synthetic phenolic antioxidant (SPA), has been used as a food additive. However, BHA acts as an environmental hormone, i.e., endocrine disruptor. Here, we investigated BHA-induced male reproductive dysfunction in mouse Leydig and Sertoli cells. We found that BHA suppressed proliferation and induced cell cycle arrest in TM3 and TM4 cells. Furthermore, we investigated mitochondrial permeabilization, expression profiles of pro-apoptotic and anti-apoptotic proteins, calcium influx, and endoplasmic reticulum (ER) stress in testicular cells after BHA treatment. The results indicated that BHA-mediated calcium dysregulation and ER stress downregulated steroidogenesis- and spermatogenesis-related genes in mouse testis cell lines. Additionally, proliferation of both TM3 and TM4 cells in response to BHA treatment was regulated via the Mapk and Akt signaling pathways. Therefore, constant BHA exposure may lead to testicular toxicity via mitochondrial dysfunction, ER stress, and abnormal calcium levels in the testis.

Original language	English
Article number	134775
Journal	Science of the Total Environment
Volume	702
DOIs	https://doi.org/10.1016/j.scitotenv.2019.134775
Publication status	Published - 2020 Feb 1

Bibliographical note

Funding Information:
This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare (grant number: HI17C0929 ), and the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (MSIT) (No. 2018R1C1B6009048 ).

Publisher Copyright:
© 2019 Elsevier B.V.

Keywords

BHA
ER stress
Leydig cell
Mitochondrial apoptosis
Sertoli cell

ASJC Scopus subject areas

Environmental Engineering
Environmental Chemistry
Waste Management and Disposal
Pollution

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10.1016/j.scitotenv.2019.134775

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title = "Butylated hydroxyanisole induces testicular dysfunction in mouse testis cells by dysregulating calcium homeostasis and stimulating endoplasmic reticulum stress",

abstract = "Butylated hydroxyanisole (BHA), a synthetic phenolic antioxidant (SPA), has been used as a food additive. However, BHA acts as an environmental hormone, i.e., endocrine disruptor. Here, we investigated BHA-induced male reproductive dysfunction in mouse Leydig and Sertoli cells. We found that BHA suppressed proliferation and induced cell cycle arrest in TM3 and TM4 cells. Furthermore, we investigated mitochondrial permeabilization, expression profiles of pro-apoptotic and anti-apoptotic proteins, calcium influx, and endoplasmic reticulum (ER) stress in testicular cells after BHA treatment. The results indicated that BHA-mediated calcium dysregulation and ER stress downregulated steroidogenesis- and spermatogenesis-related genes in mouse testis cell lines. Additionally, proliferation of both TM3 and TM4 cells in response to BHA treatment was regulated via the Mapk and Akt signaling pathways. Therefore, constant BHA exposure may lead to testicular toxicity via mitochondrial dysfunction, ER stress, and abnormal calcium levels in the testis.",

keywords = "BHA, ER stress, Leydig cell, Mitochondrial apoptosis, Sertoli cell",

author = "Jiyeon Ham and Whasun Lim and Seungkwon You and Gwonhwa Song",

note = "Funding Information: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare (grant number: HI17C0929 ), and the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (MSIT) (No. 2018R1C1B6009048 ). Publisher Copyright: {\textcopyright} 2019 Elsevier B.V.",

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doi = "10.1016/j.scitotenv.2019.134775",

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journal = "Science of the Total Environment",

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AU - Ham, Jiyeon

AU - Lim, Whasun

AU - You, Seungkwon

AU - Song, Gwonhwa

N1 - Funding Information: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare (grant number: HI17C0929 ), and the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (MSIT) (No. 2018R1C1B6009048 ). Publisher Copyright: © 2019 Elsevier B.V.

PY - 2020/2/1

Y1 - 2020/2/1

N2 - Butylated hydroxyanisole (BHA), a synthetic phenolic antioxidant (SPA), has been used as a food additive. However, BHA acts as an environmental hormone, i.e., endocrine disruptor. Here, we investigated BHA-induced male reproductive dysfunction in mouse Leydig and Sertoli cells. We found that BHA suppressed proliferation and induced cell cycle arrest in TM3 and TM4 cells. Furthermore, we investigated mitochondrial permeabilization, expression profiles of pro-apoptotic and anti-apoptotic proteins, calcium influx, and endoplasmic reticulum (ER) stress in testicular cells after BHA treatment. The results indicated that BHA-mediated calcium dysregulation and ER stress downregulated steroidogenesis- and spermatogenesis-related genes in mouse testis cell lines. Additionally, proliferation of both TM3 and TM4 cells in response to BHA treatment was regulated via the Mapk and Akt signaling pathways. Therefore, constant BHA exposure may lead to testicular toxicity via mitochondrial dysfunction, ER stress, and abnormal calcium levels in the testis.

AB - Butylated hydroxyanisole (BHA), a synthetic phenolic antioxidant (SPA), has been used as a food additive. However, BHA acts as an environmental hormone, i.e., endocrine disruptor. Here, we investigated BHA-induced male reproductive dysfunction in mouse Leydig and Sertoli cells. We found that BHA suppressed proliferation and induced cell cycle arrest in TM3 and TM4 cells. Furthermore, we investigated mitochondrial permeabilization, expression profiles of pro-apoptotic and anti-apoptotic proteins, calcium influx, and endoplasmic reticulum (ER) stress in testicular cells after BHA treatment. The results indicated that BHA-mediated calcium dysregulation and ER stress downregulated steroidogenesis- and spermatogenesis-related genes in mouse testis cell lines. Additionally, proliferation of both TM3 and TM4 cells in response to BHA treatment was regulated via the Mapk and Akt signaling pathways. Therefore, constant BHA exposure may lead to testicular toxicity via mitochondrial dysfunction, ER stress, and abnormal calcium levels in the testis.

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Butylated hydroxyanisole induces testicular dysfunction in mouse testis cells by dysregulating calcium homeostasis and stimulating endoplasmic reticulum stress

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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