ToxSci Advance Access originally published online on February 23, 2005
Toxicological Sciences 2005 85(1):743; doi:10.1093/toxsci/kfi131
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Prenatal Exposure to Phthalates and Intrauterine Inflammation: A Unifying Hypothesis
,1
* Division of Neonatology, Ospedale Perrino, Brindisi, Italy; Clinical Physiology Institute, National Research Council of Italy (IFC-CNR), Lecce Section, Italy; Laboratory of General Physiology, Department of Biological and Environmental Sciences and Technology, University of Lecce; and Neonatal Intensive Care Unit, Azienda Ospedaliera Senese, Siena, Italy
1 To whom correspondence should be addressed at Division of Neonatology, Perrino Hospital, S.S. per Mesagne, 72100 Brindisi, Italy. Tel:+39-0831-537471; Fax:+39-0831–537861. E-mail: gilatini{at}tin.it.
Received February 10, 2004; accepted February 13, 2005
We read with great interest the recent paper by Xu et al. (2005)
, showing that phthalates alter rat placental essential fatty acids (EFA) homeostasis via peroxisome proliferator-activated receptor (PPAR) overexpression, potentially leading to abnormal fetal development. Acumulating evidence from human and animal studies indicates that EFA of both the n-3 and n-6 series, as well as their eicosanoid metabolites, play important and modifiable roles in gestational duration and parturition (Allen and Harris, 2001). We have recently documented that di-2-ethyhexyl phthalate (DEHP) exposure begins during intrauterine life and is associated with a shorter duration of pregnancy (Latini et al., 2003). Because phthalates induce and activate PPAR
and 
(Hurst and Waxman, 2003), and because they possess an intrinsic pro-inflammatory activity (Gourlay et al., 2003), we suggest their possible role in inducing and/or potentiating an intrauterine inflammatory response.
Cyclooxygenase (COX)-2 is an inducible enzyme known to be upregulated by growth factors, lypopolysaccharide (LPS), and cytokines during inflammatory processes (Perkins and Kniss, 1997). Exposure to LPS in pregnant animals is a known experimental model for histological chorioamnionitis (HCA), a leading cause of preterm birth (Newnham et al., 2002).
Because some natural PPAR agonists induce COX-2 in epithelial cells (Meade et al., 1999), we propose that phthalates may lead to shortening of human pregnancy by establishing an intrauterine inflammatory process by inducing, via PPAR, the expression of COX-2 and/or the release of related prostaglandins. If this hypothesis is correct, maternal supplementation of very-long-chain n-3 polyunsaturated fatty acids (PUFAs), known anti-inflammatory agents (Simopoulos, 2002), during pregnancy (Helland et al., 2003) could potentially counteract the adverse effects of phthalate exposure in the human fetus.
REFERENCES
Allen, K. G., and Harris, M. A. (2001). The role of n-3 fatty acids in gestation and parturition. Exp. Biol. Med. (Maywood) 226, 498–506.
Gourlay, T., Samartzis, I., Stefanou, D., and Taylor, K. (2003). Inflammatory response of rat and human neutrophils exposed to di-(2-ethyl-hexyl)-phthalate-plasticized polyvinyl chloride. Artif. Organs 27, 256–260.[CrossRef][Web of Science][Medline]
Helland, I. B., Smith, L., Saarem, K., Saugstad, O. D., and Drevon, C. A. (2003). Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children's IQ at 4 years of age. Pediatrics 111, e39–44.
Hurst, C. H., and Waxman, D. J. (2003). Activation of PPARalpha and PPARgamma by environmental phthalate monoesters. Toxicol. Sci. 74, 297–308. Epub 2003 Jun 12.
Latini, G., De Felice, C., Presta, G., Del Vecchio, A., Paris, I., Ruggieri, F., and Mazzeo, P. (2003). In utero exposure to di-(2-ethylhexyl)phthalate and duration of human pregnancy. Environ. Health Perspect. 111, 1783–1785.[Web of Science][Medline]
Meade, E. A., McIntyre, T. M., Zimmerman, G. A., and Prescott, S. M. (1999). Peroxisome proliferators enhance cyclooxygenase-2 expression in epithelial cells. J. Biol. Chem. 274, 8328–8334.
Newnham, J. P., Moss, T. J., Kramer, B. W., Nitsos, I., Ikegami, M., and Jobe, A. H. (2002). The fetal maturational and inflammatory responses to different routes of endotoxin infusion in sheep. Am. J. Obstet. Gynecol. 186, 1062–1068.[CrossRef][Medline]
Perkins, D. J., and Kniss, D. A. (1997). Tumor necrosis factor-alpha promotes sustained cyclooxygenase-2 expression: Attenuation by dexamethasone and NSAIDs. Prostaglandins 54, 727–743.[CrossRef][Web of Science][Medline]
Simopoulos, A. (2002). Omega-3 fatty acids in inflammation and autoimmune disease. J. Am. Coll. Nutr. 21, 495–505.
Xu, Y., Cook, T. J., and Knipp, G. T. (2005). Effects of di-( 2-ethylhexyl)-phthalate (DEHP) and its metabolites on fatty acid homeostasis regulating proteins in rat placental HRP-1 trophoblast cells. Toxicol. Sci. 12, 12.
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