Respiratory and olfactory cytotoxicity of inhaled 2,3-pentanedione in Sprague-Dawley rats.
Flavorings-related lung disease is a potentially disabling disease of food industry workers associated with exposure to the α-diketone butter flavoring, diacetyl (2,3-butanedione). To investigate the hypothesis that another α-diketone flavoring, 2,3-pentanedione, would cause airway damage, rats that inhaled air, 2,3-pentanedione (112, 241, 318, or 354 ppm), or diacetyl (240 ppm) for 6 hours were sacrificed the following day. Rats inhaling 2,3-pentanedione developed necrotizing rhinitis, tracheitis, and bronchitis comparable to diacetyl-induced injury. To investigate delayed toxicity, additional rats inhaled 318 (range, 317.9-318.9) ppm 2,3-pentanedione for 6 hours and were sacrificed 0 to 2, 12 to 14, or 18 to 20 hours after exposure. Respiratory epithelial injury in the upper nose involved both apoptosis and necrosis, which progressed through 12 to 14 hours after exposure. Olfactory neuroepithelial injury included loss of olfactory neurons that showed reduced expression of the 2,3-pentanedione-metabolizing enzyme, dicarbonyl/L-xylulose reductase, relative to sustentacular cells. Caspase 3 activation occasionally involved olfactory nerve bundles that synapse in the olfactory bulb (OB). An additional group of rats inhaling 270 ppm 2,3-pentanedione for 6 hours 41 minutes showed increased expression of IL-6 and nitric oxide synthase-2 and decreased expression of vascular endothelial growth factor A in the OB, striatum, hippocampus, and cerebellum using real-time PCR. Claudin-1 expression increased in the OB and striatum. We conclude that 2,3-pentanedione is a respiratory hazard that can also alter gene expression in the brain.
Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA. ahubbs@cdc.gov
Ann F
AF
Hubbs
Amy M
AM
Cumpston
W Travis
WT
Goldsmith
Lori A
LA
Battelli
Michael L
ML
Kashon
Mark C
MC
Jackson
David G
DG
Frazer
Jeffrey S
JS
Fedan
Madhusudan P
MP
Goravanahally
Vincent
V
Castranova
Kathleen
K
Kreiss
Patsy A
PA
Willard
Sherri
S
Friend
Diane
D
Schwegler-Berry
Kara L
KL
Fluharty
Krishnan
K
Sriram
D000280:Administration, Inhalation; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003931:Diacetyl / Q000633:toxicity; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009830:Olfactory Bulb / Q000187:drug effects / Q000473:pathology*; D051842:Olfactory Marker Protein / Q000378:metabolism; D010422:Pentanones / Q000008:administration & dosage* / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012137:Respiratory System / Q000473:pathology*; D013194:Staining and Labeling; D013401:Sugar Alcohol Dehydrogenases / Q000378:metabolism; D013997:Time Factors
D015820:Cadherins; D051842:Olfactory Marker Protein; D010422:Pentanones; D012333:RNA, Messenger; D013401:Sugar Alcohol Dehydrogenases; C023300:L-xylulose reductase; D053148:Caspase 3; D003931:Diacetyl; C013186:2,3-pentanedione