Benzo[a]pyrene exposure in muscle triggers sarcopenia through aryl hydrocarbon receptor-mediated reactive oxygen species production

Shou-En Wu; Ju-Chun Hsu; Yung-Lung Chang; Hsiao-Chi Chuang; Yi-Lin Chiu; Wei-Liang Chen

doi:10.1016/j.ecoenv.2022.113599

Benzo[a]pyrene exposure in muscle triggers sarcopenia through aryl hydrocarbon receptor-mediated reactive oxygen species production

Ecotoxicol Environ Saf. 2022 Jul 1:239:113599. doi: 10.1016/j.ecoenv.2022.113599. Epub 2022 May 11.

Authors

Shou-En Wu¹, Ju-Chun Hsu², Yung-Lung Chang², Hsiao-Chi Chuang³, Yi-Lin Chiu², Wei-Liang Chen⁴

Affiliations

¹ Department of Dermatology, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei City, Taiwan (R.O.C); Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei City, Taiwan (R.O.C); Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, Taipei, Taiwan (R.O.C).
² Department of Biochemistry, National Defense Medical Center, Taiwan (R.O.C).
³ School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan (R.O.C); Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan (R.O.C); Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan (R.O.C).
⁴ Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei City, Taiwan (R.O.C); Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, Taipei, Taiwan (R.O.C); Department of Biochemistry, National Defense Medical Center, Taiwan (R.O.C). Electronic address: weiliang0508@gmail.com.

PMID: 35567930
DOI: 10.1016/j.ecoenv.2022.113599

Abstract

Background: Benzo[a]pyrene (BaP), a toxic carcinogen, is associated with various adverse effects but is rarely discussed in muscle-related disorders. This study investigated in vitro and in vivo effects triggered by BaP exposure in muscles and hypothesized that exposure might induce conditions similar to sarcopenia due to the shared mechanism of oxidative stress. In vitro experiments used C2C12 mouse myoblasts to examine effects induced by BaP exposure in control (untreated) and BaP-treated (10 µM/ml) muscle cells. An established TNF-α-treated sarcopenia model was utilized to verify our results. In vivo experiments compared immunohistochemical staining of sarcopenia-related markers in rats exposed to clean air and polluted air.

Results: In C2C12 cells, after 2-72 h of BaP exposure, elevated mRNA and protein expressions were observed in aryl hydrocarbon receptor (AhR) and cytochrome P450 1A1, subsequently in ROS (NOX2 and NOX4) production, inflammatory cytokines (IL-6, TNF-α, and NF-kB), and proteins mediating apoptotic cell death (caspase-3 and PARP). Two myokines also altered mRNA and protein expressions akin to changes in sarcopenia, namely decreased irisin levels and increased myostatin levels. In addition, N-acetylcysteine, a well-known antioxidant, led to decrease in oxidative markers induced by BaP. The validation by TNF-α-treated sarcopenia model revealed comparable biological responses in either TNF-α or BaP treated C2C12 cells. In vivo experiments with rats exposed to air pollution showed increased expression of BaP, AhR, 8-hydroxydeoxyguanosine, and myostatin and decreased irisin expression in immunohistochemical staining.

Conclusions: Our results suggest that BaP exerts deleterious effects on the muscle, leading to conditions indicative of sarcopenia. Antioxidant supplementation may be a treatment option for BaP-induced sarcopenia, but further validation studies are needed.

Keywords: Aryl hydrocarbon receptor; Benzo[a]pyrene; Muscle; Polycyclic aromatic hydrocarbon; Reactive oxygen species; Sarcopenia.

MeSH terms

Animals
Antioxidants
Benzo(a)pyrene* / toxicity
Fibronectins
Mice
Muscles / metabolism
Myostatin
RNA, Messenger / metabolism
Rats
Reactive Oxygen Species / metabolism
Receptors, Aryl Hydrocarbon / genetics
Receptors, Aryl Hydrocarbon / metabolism
Sarcopenia* / chemically induced
Tumor Necrosis Factor-alpha / genetics

Substances

Antioxidants
Fibronectins
Myostatin
RNA, Messenger
Reactive Oxygen Species
Receptors, Aryl Hydrocarbon
Tumor Necrosis Factor-alpha
Benzo(a)pyrene