Dysregulation of the mTOR pathway by mechlorethamine. (1st March 2023)

• Record Type: Journal Article
• Authors: Rao, Trishaal Janardhanam Raghavendra; Mao, Ganming; Cuffari, Benedette J.; Billack, Blase
• Is Part Of: Toxicology. Volume 486(2023)
• Publication Date: 2023-03-01
• Subjects: SM Sulfur Mustard -- NM Nitrogen Mustard -- HN2 Mechlorethamine -- MEVM Mouse ear vesicant model -- mTOR mammalian target of rapamycin -- mTORC1 mammalian target of rapamycin complex 1 -- RAPTOR Regulatory-associated protein of mTOR -- 4E-BP1 Eukaryotic translation initiation factor 4E-binding protein 1 -- S6 Ribosomal protein S6; Mechlorethamine -- Nitrogen mustard -- MTOR -- Phospho 4E-BP1 -- Phospho S6 ribosomal protein -- Raptor; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2023.153434
• Languages: English
• ISSNs: 0300-483X

Abstract

Abstract: Mechlorethamine (HN2) is a derivative of the chemical warfare agent sulfur mustard (SM) and cutaneous exposure to HN2 is associated with dermal-epidermal junction (DEJ) disruption (vesication). The primary purpose of the present study was to investigate the effect of HN2 on the mammalian target of rapamycin (mTOR) signaling pathway using an in vivo mouse ear vesicant model (MEVM). To this end, the ears of male C57BL/ 6 J mice were exposed to a single topical dose of HN2 (100 mM) or vehicle control (DMSO). Mice were then euthanized 30 min, 1 h or 24 h following exposure. Mouse ear skin exposed to HN2 and biopsied 24 h thereafter exhibited increased tissue expression of Raptor, an important member of the mTORC1 complex, relative to vehicle treated samples. HN2 reduced the downstream effectors phospho S6 (Ser 240/244) ribosomal protein and phospho 4E-BP1 (Thr 37/46) of the mTOR pathway in the epidermis at 30 min, 1 h and 24 h following HN2 exposure but not in the dermis. These results support the hypothesis that HN2-mediated cutaneous toxicity involves dysregulation of the mTOR signaling pathway in the epidermis. Highlights: HN2 alters expression of Raptor in the epidermis of mouse ear skin. HN2 decreases phosphorylated S6 ribosomal protein in mouse ear and human KB-3–1 cells. HN2 decreases phosphorylated 4E-BP1 in mouse ear but not in KB-3–1 cells. DMSO as a vehicle induces transient tissue edema at 30 min and 1 h but not at 24 h.