Sulfur mustard analog induces oxidative stress and activates signaling cascades in the skin of SKH-1 hairless mice.
A monofunctional analog of the chemical warfare agent sulfur mustard (HD), 2-chloroethyl ethyl sulfide (CEES), induces tissue damage similar to HD. Herein we studied the molecular mechanisms associated with CEES-induced skin inflammation and toxicity in SKH-1 hairless mice. Topical CEES exposure caused an increase in oxidative stress as observed by enhanced 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid)-1-pyrroline N-oxide protein adduct formation and an increase in protein oxidation. The CEES-induced increase in the formation of 8-oxo-2-deoxyguanosine indicated DNA oxidation. CEES exposure instigated an increase in the phosphorylation of mitogen-activated protein kinases (MAPKs; ERK1/2, JNK, and p38). After CEES exposure, a significant increase in the phosphorylation of Akt at Ser473 and Thr308 was observed as well as upregulation of its upstream effector, PDK1, in mouse skin tissue. Subsequently, CEES exposure caused activation of AP-1 family proteins and the NF-kappaB pathway, including phosphorylation and degradation of IkappaBalpha in addition to phosphorylation of the NF-kappaB essential modulator. Collectively, our results indicate that CEES induces oxidative stress and the activation of the transcription factors AP-1 and NF-kappaB via upstream signaling pathways including MAPKs and Akt in SKH-1 hairless mouse skin. These novel molecular targets could be supportive in the development of prophylactic and therapeutic interventions against HD-related skin injury.
Pal
Arttatrana
A
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado at Denver, Aurora, CO 80045, USA.
Tewari-Singh
Neera
N
Gu
Mallikarjuna
M
Agarwal
Chapla
C
Huang
Jie
J
Day
Brian J
BJ
White
Carl W
CW
Agarwal
Rajesh
R
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D003497:Cyclic N-Oxides / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D003839:Deoxyadenosines / Q000378:metabolism; D017453:Dermatitis, Irritant / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008812:Mice, Hairless; D009151:Mustard Gas / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016328:NF-kappa B / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000096:biosynthesis / Q000235:genetics; D010084:Oxidation-Reduction / Q000187:drug effects; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation
D000447:Aldehydes; D003497:Cyclic N-Oxides; D003839:Deoxyadenosines; D016328:NF-kappa B; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D018808:Transcription Factor AP-1; C095292:5,5-dimethyl-2-phenyl-1-pyrroline-N-oxide; C078251:2'-deoxy-7,8-dihydro-8-oxoadenosine; C031278:2-chloroethyl ethyl sulfide; D051058:Oncogene Protein v-akt; D017346:Protein Serine-Threonine Kinases; C027576:4-hydroxy-2-nonenal; D009151:Mustard Gas