title: Response of rats to low levels of sarin.
abstract: The purpose of this study was to determine whether exposure to levels of sarin causing no overt clinical signs would cause more subtle, adverse health effects that persisted after the exposure ended. Inhalation exposures of male Fischer 344 rats to 0, 0.2, or 0.4 mg/m(3) of sarin for 1 h/day for 1, 5, or 10 days under normal (25 degrees C) and heat-stressed (32 degrees C) conditions were completed and observations were made at 1 day and 1 month after the exposures. The sarin exposures had no observed effects on body weight, respiration rate, and minute volume during exposure nor in body temperature and activity during the 30-day recovery period. There was no evidence of cellular changes in brain determined by routine histopathology nor of any increase in apoptosis. Brain mRNA for interleukin (IL)-1beta, tumor necrosis factor-alpha, and IL-6 was increased in a dose-dependent manner. Autoradiographic studies demonstrated that M1 cholinergic receptor site densities were unchanged at 1 day after repeated exposures with or without heat stress. At 30 days, there was a decrease in M1 receptors in the olfactory tubercle (with and without heat), and, with heat stress, M1 sites also decreased in a dose-dependent manner in the frontal cortex, anterior olfactory nucleus, and hippocampus. M3 receptor sites were not affected by sarin exposure alone. In the presence of heat stress, there was an upregulation in binding site densities in the frontal cortex, olfactory tubercle, anterior nucleus, and striatum immediately after exposure, and these effects persisted at 30 days. Although red blood cell acetylcholinesterase (AChE) was not greatly inhibited by the 1-day exposure, there were 30 and 60% inhibitions after repeated exposures at the low and high doses, respectively. Histochemical staining for AChE demonstrated that sarin exposure alone reduced AChE in the cerebral cortex, striatum, and olfactory bulb. Sarin exposure under heat stress reduced AChE staining in the hippocampus, an area important for memory function. Thus, repeated exposures under heat-stress conditions, to levels of sarin that would not be noticed clinically, resulted in delayed development of brain alterations in cholinergic receptor subtypes that may be associated with memory loss and cognitive dysfunction.
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.
authors.forename: Rogene F
authors.initials: RF
authors.lastname: Henderson
authors.forename: Edward B
authors.initials: EB
authors.lastname: Barr
authors.forename: Walter B
authors.initials: WB
authors.lastname: Blackwell
authors.forename: Connie R
authors.initials: CR
authors.lastname: Clark
authors.forename: Carole A
authors.initials: CA
authors.lastname: Conn
authors.forename: Roma
authors.initials: R
authors.lastname: Kalra
authors.forename: Thomas H
authors.initials: TH
authors.lastname: March
authors.forename: Mohan L
authors.initials: ML
authors.lastname: Sopori
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Tesfaigzi
authors.forename: Margaret G
authors.initials: MG
authors.lastname: Ménache
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Mash
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D016207:Cytokines / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects / Q000502:physiology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011976:Receptors, Muscarinic / Q000032:analysis / Q000187:drug effects; D012524:Sarin / Q000633:toxicity*
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D016207:Cytokines; D011976:Receptors, Muscarinic; D012524:Sarin; D000110:Acetylcholinesterase