Academic journal article Environmental Health Perspectives

Transcriptional Biomarkers of Steroidogenesis and Trophoblast Differentiation in the Placenta in Relation to Prenatal Phthalate Exposure

Academic journal article Environmental Health Perspectives

Transcriptional Biomarkers of Steroidogenesis and Trophoblast Differentiation in the Placenta in Relation to Prenatal Phthalate Exposure

Article excerpt

BACKGROUND: Phthalates can alter steroidogenesis and peroxisome proliferator-activated receptor gamma (PPAR[gamma])-mediated transcription in rodent tissues. The placenta offers a rich source of biomarkers to study these relationships in humans.

OBJECTIVE: We evaluated whether gestational phthalate exposures in humans were associated with altered human placental steroidogenesis and trophoblast differentiation as measured by markers of mRNA transcription.

METHODS: We measured seven target genes in placentas collected from 54 Dominican and African-American women at delivery in New York City using quantitative real-time polymerase chain reaction (qPCR), normalized to 18S rRNA. qPCR results for the target genes were log-transformed, converted to .Z-scores, and grouped into two functional pathways: steroidogenesis (aromatase, cholesterol side chain cleavage enzyme, 17[beta]-hydroxysteroid dehydrogenase type 1, and cytochrome P450 IB1) and trophoblast differentiation (PPAR[gamma], aryl hydrocarbon receptor, and human chorionic gonadotropin). Repeated measures models were used to evaluate the association of phthalate metabolites measured in third-trimester urine samples with each group of target genes, accounting for correlation among the genes within a pathway.

RESULTS: Higher urinary concentrations of five phthalate metabolites were associated with lower expression of the target genes reflecting trophoblast differentiation. Results were less consistent for genes in the steroidogenesis pathway and suggested a nonlinear dose-response pattern for some phthalate metabolites.

CONCLUSIONS: We observed a significant association between prenatal exposure to phthalates and placental gene expression within two pathways. Further studies are warranted to understand the significance of this association with respect to fetal development and placental function.

KEY WORDS: epidemiology, gene expression, phthalates, placenta, pregnancy, prenatal, steroidogenesis, trophoblast differentiation. Environ Health Perspect 118:291-296 (2010). doi:10.1289/ ehp.0900788 available via [Online 15 September 2009]


Phthalates are synthetic chemicals used in plastics, personal care products, and building materials. Phthalates are metabolized and excreted in urine 12-48 hr after exposure (Koch et al. 2005). Urinary phthalate metabolites measured have been used extensively as biomarkers of human exposure (Hauser and Calafat 2005).

The metabolites of at least four phthalates can induce a wide range of responses with potential relevance to human reproduction and development (Hauser and Calafat 2005; Swan 2008). When given to rats in utero, di(2-ethylhexyl) phthalate (DEHP), di-n-bu-tyl phthalate (DnBP), diisobutyl phthalate (DiBP), and butylbenzyl phthalate (BBzP) altered steroidogenesis and produced a pheno-type that involved reduced testosterone synthesis in fetal Leydig cells and concomitant effects on the male offspring resembling the testicular dysgenesis syndrome (Barlow et al. 2003; Ema et al. 2000; Mylchreest et al. 2000; Saillenfait et al. 2008; Sharpe 2001). Similarly, in female rats, DEHP, DnBP, and DiBP produced alterations in ovarian steroidogenesis, partly mediated by CYP19 (aromatase) inhibition and progesterone inhibition (Boberg et al. 2008; Davis et al. 1994a, 1994b; Lovekamp and Davis 2001).

The peroxisome proliferator-activated receptor protein gamma (PPAR[gamma]) is a master regulator of several reproductive and developmental pathways, including steroidogenesis, differentiation, fatty acid uptake and transport, and inflammation related to parturition (Froment et al. 2006; Schaiff et al. 2006). PPAR[gamma] is expressed in the human trophoblast and is essential to basic placental development and function (Fournier et al. 2007). Agonism of PPAR[gamma] by phthalate metabolites has been proposed as a mechanism of action (Lovekamp-Swan et al. …

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