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ToxSci Advance Access originally published online on January 12, 2005
Toxicological Sciences 2005 84(2):287-300; doi:10.1093/toxsci/kfi083
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Toxicological Sciences vol. 84 no. 2 © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Effects of Di-(2-Ethylhexyl)-Phthalate (DEHP) and Its Metabolites on Fatty Acid Homeostasis Regulating Proteins in Rat Placental HRP-1 Trophoblast Cells

Yan Xu, Thomas J. Cook and Gregory T. Knipp1

Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey 08854

Received September 29, 2004; accepted December 15, 2004

Di-(2-ethylhexyl)-phthalate (DEHP) is a widely used plasticizer and ubiquitous environmental contaminant. The potential health hazards, including teratogenicity, from exposure to DEHP may be related to the role of DEHP or its metabolites in the trans-activation of peroxisome proliferator-activated receptors (PPARs). Fetal essential fatty acid (EFA) homeostasis is controlled by directional transfer across the placenta through a highly regulated process, including PPAR activation. Using HRP-1 rat trophoblastic cells, the effects of DEHP and two of its metabolites, mono-(2-ethylhexyl)-phthalate (MEHP) and 2-ethylhexanoic acid (EHA), on the mRNA and protein expression of the three known PPAR isoforms ({alpha}, ß, and {gamma}), fatty acid transport protein 1 (FATP1), plasma membrane fatty acid binding protein (FABPpm), and the heart cytoplasmic fatty acid binding protein (HFABP) were investigated. This study also investigated the functional effects of exposure on the uptake and transport of six long chain fatty acids (LCFAs): arachidonic acid (AA), docosahexaenoic acid (DHA), linoleic acid (LA), {alpha}-linolenic acid (ALA), oleic acid (OA), and stearic acid (SA). In the presence of DEHP, MEHP, and EHA, the expression of PPAR{alpha}, PPAR{gamma}, FATP1, and HFABP were up-regulated in a dose- and time- dependent manner, while PPARß and FABPpm demonstrated variable expression. The uptake rates of EFAs (AA, DHA, LA, ALA) increased significantly upon exposure, and the transport of AA ({omega}-6) and DHA ({omega}-3) were directionally induced. These results suggest that DEHP, MEHP, and EHA can influence EFA transfer across HRP-1 cells, implying that these compounds may alter placental EFA homeostasis and potentially result in abnormal fetal development.

Key Words: phthalates; rat; placenta; HRP-1; fatty acid; transport; PPAR.


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