Evaluation of the potential of triethanolamine to alter hepatic choline levels in female B6C3F1 mice.
Triethanolamine (TEA), a widely used nongenotoxic alcohol-amine, has recently been reported to cause an increased incidence of liver tumors in female B6C3F1 mice, but not in males nor in Fischer 344 rats. Choline deficiency induces liver cancer in rodents, and TEA could compete with choline uptake into tissues. The potential of TEA to cause choline deficiency in the liver of these mice as a mode of tumorigenesis was investigated. Groups of female B6C3F1 mice were administered 0 (vehicle) or a maximum tolerated dosage (MTD) of 1000 mg/kg/day TEA (Trial I) and 0, 10, 100, 300, or 1000 mg/kg/day TEA (Trial II) in acetone vehicle via skin painting 5 days/week for 3 weeks. Female CDF(R) rats were also administered 0 or an MTD dosage of 250 mg/kg/day TEA (Trial II) in a similar manner. No clinical signs of toxicity were noted, and upon sacrifice, levels of hepatic choline, its primary storage form, phosphocholine (PCho), and its primary oxidation product, betaine, were determined. A statistically significant decrease in PCho and betaine, was observed at the high dosage (26-42%) relative to controls and a dose-related, albeit variable, decrease was noted in PCho levels. Choline levels were also decreased 13-35% at the high dose level in mice. No changes in levels of choline or metabolites were noted in treated rats. A subsequent evaluation of the potential of TEA to inhibit the uptake of (3)H-choline by cultured Chinese Hamster Ovary Cells revealed a dose-related effect upon uptake. It was concluded that TEA may cause liver tumors in mice via a choline-depletion mode of action and that this effect is likely caused by the inhibition of choline uptake by cells.
Stott
W T
WT
Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 84674, USA. wstott@dow.com
Radtke
B J
BJ
Linscombe
V A
VA
Mar
M-H
MH
Zeisel
S H
SH
D000287:Administration, Topical; D000818:Animals; D001622:Betaine / Q000032:analysis / Q000378:metabolism; D016466:CHO Cells; D002478:Cells, Cultured; D002794:Choline / Q000032:analysis / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004983:Ethanolamines / Q000633:toxicity*; D005260:Female; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D010767:Phosphorylcholine / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D014316:Tritium
D004983:Ethanolamines; D014316:Tritium; D010767:Phosphorylcholine; D001622:Betaine; C009546:triethanolamine; D002794:Choline