Teratogenicity of di(2-ethylhexyl) phthalate, 2-ethylhexanol, 2-ethylhexanoic acid, and valproic acid, and potentiation by caffeine.
It is hypothesized that the teratogen di(2-ethylhexyl) phthalate (DEHP) acts by in vivo hydrolysis to 2-ethylhexanol (2-EHXO), which in turn is metabolized to 2-ethylhexanoic acid (2-EHXA), the proximate teratogen. Teratological studies were conducted with Wistar rats, with administration of these agents on day 12 of gestation. On an equimolar basis DEHP was least potent, 2-EHXO was intermediate, and 2-EXHA was the most potent of the three agents, which is consistent with the hypothesis. Similarity in the types of defects found with these agents also suggests a common mechanism, with 2-EHXA as the proximate teratogen. All three agents were potentiated by caffeine. Valproic acid, which is an isomer of 2-EXHA, also produced similar defects, and was approximately twice as potent as 2-EHXA.
D000014:Abnormalities, Drug-Induced; D000818:Animals; D002110:Caffeine / Q000633:toxicity*; D002208:Caproates / Q000378:metabolism / Q000633:toxicity*; D004051:Diethylhexyl Phthalate / Q000378:metabolism / Q000633:toxicity*; D004357:Drug Synergism; D005260:Female; D000441:Hexanols / Q000378:metabolism / Q000633:toxicity*; D008431:Maternal-Fetal Exchange; D010795:Phthalic Acids / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D014635:Valproic Acid / Q000633:toxicity*
D002208:Caproates; D000441:Hexanols; D010795:Phthalic Acids; C040668:2-ethylhexanoic acid; D002110:Caffeine; D014635:Valproic Acid; D004051:Diethylhexyl Phthalate; C034017:2-ethylhexanol