Interactions of Dichlorodiphenyltrichloroethane (DDT) and Dichlorodiphenyldichloroethylene (DDE) With Skeletal Muscle Ryanodine Receptor Type 1
Autor: | Kim M Truong, Isaac N. Pessah, Gennady Cherednichenko |
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Rok vydání: | 2019 |
Předmět: |
Male
Molecular Biochemical and Systems Toxicology Agonist medicine.medical_specialty medicine.drug_class Dichlorodiphenyl Dichloroethylene Muscle Fibers Skeletal Toxicology DDT Mice chemistry.chemical_compound Caffeine Internal medicine medicine Animals Humans Muscle Skeletal Receptor RYR1 Sex Characteristics Myogenesis Ryanodine receptor Skeletal muscle Ryanodine Receptor Calcium Release Channel musculoskeletal system Mice Inbred C57BL HEK293 Cells Endocrinology medicine.anatomical_structure Dichlorodiphenyldichloroethylene chemistry Endocrine disruptor Calcium Female Rabbits tissues |
Zdroj: | Toxicol Sci |
ISSN: | 1096-0929 1096-6080 |
Popis: | Dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) are ubiquitous in the environment and detected in tissues of living organisms. Although DDT owes its insecticidal activity to impeding closure of voltage-gated sodium channels, it mediates toxicity in mammals by acting as an endocrine disruptor (ED). Numerous studies demonstrate DDT/DDE to be EDs, but studies examining muscle-specific effects mediated by nonhormonal receptors in mammals are lacking. Therefore, we investigated whether o,p′-DDT, p,p′-DDT, o,p′-DDE, and p,p′-DDE (DDx, collectively) alter the function of ryanodine receptor type 1 (RyR1), a protein critical for skeletal muscle excitation-contraction coupling and muscle health. DDx (0.01–10 µM) elicited concentration-dependent increases in [3H]ryanodine ([3H]Ry) binding to RyR1 with o,p′-DDE showing highest potency and efficacy. DDx also showed sex differences in [3H]Ry-binding efficacy toward RyR1, where [3H]Ry-binding in female muscle preparations was greater than male counterparts. Measurements of Ca2+ transport across sarcoplasmic reticulum (SR) membrane vesicles further confirmed DDx can selectively engage with RyR1 to cause Ca2+ efflux from SR stores. DDx also disrupts RyR1-signaling in HEK293T cells stably expressing RyR1 (HEK-RyR1). Pretreatment with DDx (0.1–10 µM) for 100 s, 12 h, or 24 h significantly sensitized Ca2+-efflux triggered by RyR agonist caffeine in a concentration-dependent manner. o,p′-DDE (24 h; 1 µM) significantly increased Ca2+-transient amplitude from electrically stimulated mouse myotubes compared with control and displayed abnormal fatigability. In conclusion, our study demonstrates DDx can directly interact and modulate RyR1 conformation, thereby altering SR Ca2+-dynamics and sensitize RyR1-expressing cells to RyR1 activators, which may ultimately contribute to long-term impairments in muscle health. |
Databáze: | OpenAIRE |
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