Transcriptional biomarkers of steroidogenesis and trophoblast differentiation in the placenta in relation to prenatal phthalate exposure

Abstract

Background: Phthalates can alter steroidogenesis and peroxisome proliferator-activated receptor gamma (PPARgamma)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, 17beta-hydroxysteroid dehydrogenase type 1, and cytochrome P450 1B1) and trophoblast differentiation (PPARgamma, 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.

Figure 1

Quintile plots of estimated mean Z-scores (± SE) of gene transcripts in the placental steroidogenesis pathway in relation to maternal urinary concentrations of MEHP (A), MEOHP (B), MnBP (C), and MBzP (D). C depicts a significant association between MnBP quintiles and steroidogenic gene expression (p = 0.001) and significantly different slopes among genes in relation to MnBP (p = 0.03).

Figure 2

Quintile plots of estimated mean Z-scores (± SE) of gene transcripts in the trophoblast differentiation pathway in relation to maternal urinary concentrations of MEHP (A), MEOHP (B), MnBP (C), and MBzP (D). B–D depict significant associations between MEOHP (p = 0.002), MnBP (p = 0.004), and MBzP (p = 0.01) quintiles and gene expression; C and D depict significantly different slopes among genes in relation to MnBP (p = 0.03) and MBzP (p = 0.01).