The individual and combined metabolite profiles (metabolomics) of dibutylphthalate and di(2-ethylhexyl)phthalate following a 28-day dietary exposure in rats.
Metabolite profiles (metabolomics) of plasma samples of Wistar rats dosed with di(2-ethylhexyl)phthalate (DEHP - 3000ppm) and dibutylphthalate (DBP - 150, 1000 and 7000ppm) were individually determined in 28 days dietary studies. In addition, profiles of combined exposure to 3000ppm DEHP and either 150, 1000 or 7000ppm DBP were determined. High dose levels induced more profound metabolite changes in males than in females for both compounds. At 150ppm DBP (NOEL for toxicity) there were very few (<false positives rate), inconsistent changes, demonstrating a metabolomic NOEL. A part of the total metabolite profile was consistent with a pattern of changes indicative of peroxisome proliferation, confirmed by increased cyanide-insensitive Palmitoyl-CoA oxidation. Simultaneous administration of 3000ppm DEHP and 150ppm DBP did not result in relevant changes when compared to the metabolite profile of 3000ppm DEHP alone. Co-administration of 1000ppm DBP induced marginal additional changes relative to the profile of 3000ppm DEHP alone. Simultaneous exposure to high dose levels of DEHP and DBP resulted in a profile that was significantly different compared to the individual compounds. A quantitative statistical analysis of the data revealed that the effect of combined treatment on the metabolites was less than additive.
van Ravenzwaay
B
B
BASF SE, Experimental Toxicology and Ecology, Z 470, D-67056 Ludwigshafen, Germany. bennard.ravenzwaay@basf.com
Coelho-Palermo Cunha
G
G
Strauss
V
V
Wiemer
J
J
Leibold
E
E
Kamp
H
H
Walk
T
T
Mellert
W
W
Looser
R
R
Prokoudine
A
A
Fabian
E
E
Krennrich
G
G
Herold
M
M
D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D003993:Dibutyl Phthalate / Q000633:toxicity*; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D055432:Metabolomics / Q000379:methods; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors; D053719:Tandem Mass Spectrometry; D036401:Toxicity Tests, Chronic
D015415:Biomarkers; D004785:Environmental Pollutants; D003993:Dibutyl Phthalate; D004051:Diethylhexyl Phthalate