Effects of acrylamide and 2,5-hexanedione on brain mitochondrial respiration.
The effects of acrylamide (ACR) and 2,5-hexanedione (2,5-HD) on brain mitochondrial respiration were assessed. Mitochondria were isolated from whole brains or brain regions of control and neurotoxicant-treated rats. Direct in vitro exposure of isolated brain mitochondria to ACR (1 mM final concentration) had no effect on respiration, whereas direct exposure to 2,5-HD (1 mM final concentration) inhibited state 3 respiration. Chronic treatment of rats with ACR (50 mg/kg/day x 10 days) did not affect respiration of mitochondria isolated from cortex or brainstem. However, in mitochondria from cerebellum of ACR treated rats, pyruvate + oxaloacetic acid (pyr/oaa) supported oxygen consumption was decreased significantly in both states 3 and 4. In addition, the ADP/O ratio was reduced in this brain structure. In all brain regions of 2,5-HD (400 mg/kg/day x 24 days) intoxicated rats, pyr/oaa supported state 3 respiration was reduced. Glutamate + malate (glu/mal) supported respiration was diminished only in mitochondria isolated from brain stem of 2,5-HD treated rats. In contrast, the non-neurotoxic analogs, 1,6-hexanediol and N,N'-methylene-bis-acrylamide did not alter mitochondrial respiration in parallel experiments. Thus, both ACR and 2,5-HD produce a substrate-dependent, toxicologically specific inhibition of brain mitochondrial respiration. This inhibition of mitochondrial energy production might play a role in the neurotoxic mechanisms of action for these chemicals.
Medrano
C J
CJ
College of Optometry, University of Houston, Texas 77204-6052.
LoPachin
R M
RM
D020106:Acrylamide; D000178:Acrylamides / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D006588:Hexanones / Q000633:toxicity*; D066298:In Vitro Techniques; D007659:Ketones / Q000633:toxicity*; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009422:Nervous System Diseases / Q000139:chemically induced; D010101:Oxygen Consumption / Q000187:drug effects*; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains
D000178:Acrylamides; D006588:Hexanones; D007659:Ketones; D020106:Acrylamide; C011269:2,5-hexanedione