Trimethyltin as a selective adrenal chemosympatholytic agent in vivo: effect precedes both clinical and histopathological evidence of toxicity.
Trimethyltin (TMT) is a potent neuronotoxiciant but there is little data regarding its systemic effects. In this study, female BALB/c mice were administered either 0.9% saline or 2.75 mg TMT/kg intraperitoneally (i.p.). The animals were then housed in room air or in glass chambers flushed with either 10%, 40%, or 100% oxygen. Mice were sacrificed at 4, 8, 24, and 48 h after treatment and adrenals analyzed for various neurotransmitters by ion-pairing HPLC with electrochemical detection. In addition, adrenal S-adenosylmethionine (SAM) and blood ketone bodies were determined Sections of adrenals were evaluated by electron microscopy for histopathological changes. In vivo treatment with the toxicant resulted in a significant decrease in adrenal epinephrine and norepinephrine levels as early as 8 h following treatment. This effect preceded the appearance of both clinical signs and histopathological changes in the hippocampus by 12-24 h. With exposure to TMT in room air, mouse adrenal content of epinephrine fell from 1861.3 +/- 97.3 ng/4 mg to 1493.3 +/- 137.0 ng/4 mg while norepinephrine levels fell from 779.6 +/- 32.3 ng/4 mg to 503.4 +/- 44.3 ng/4 after 8 h. Supplementation with 40% oxygen did not attenuate this effect but in the case of mice treated with TMT and housed in 100% oxygen for 48 h, actually exacerbated the adrenal epinephrine depletion. Housing in approximately half normal atmospheric oxygen (10%) neither prevented nor enhanced the effects of TMT. The epinephrine/norepinephrine ratios were: control, 2.44; TMT (room air), 1.56; TMT (10% O2), 1.72; TMT (40% O2), 1.44; TMT (100% O2), 1.07. None of the conditions used in this study caused a decrease in adrenal dopamine, 5-hydroxyindole acetic acid (5-HIAA), 5-hydroxytryptamine (5-HT) or in the level of SAM. TMT treatment significantly increased blood ketone bodies indicating additional metabolic dysfunction. The significance of these findings in relation to TMT neuronotoxicity and fatty liver syndrome are discussed.
D020155:3-Hydroxybutyric Acid; D000311:Adrenal Glands / Q000032:analysis* / Q000187:drug effects; D000818:Animals; D002395:Catecholamines / Q000032:analysis*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006885:Hydroxybutyrates / Q000097:blood; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D010100:Oxygen / Q000627:therapeutic use; D014220:Trialkyltin Compounds / Q000633:toxicity*; D014298:Trimethyltin Compounds / Q000633:toxicity*
D002395:Catecholamines; D006885:Hydroxybutyrates; D014220:Trialkyltin Compounds; D014298:Trimethyltin Compounds; C046488:trimethyltin; D010100:Oxygen; D020155:3-Hydroxybutyric Acid