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

Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA.
Environmental Health Perspectives (Impact Factor: 7.98). 02/2010; 118(2):291-6. DOI: 10.1289/ehp.0900788
Source: PubMed


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.
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.
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.
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.
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.

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Available from: Lori Hoepner, Sep 29, 2015
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    • "Phthalates are recognised to be endocrine disrupting chemicals with anti-androgenic properties (Lyche et al. 2009). They cross the placenta to the developing fetus (Mose et al. 2007, Adibi et al. 2010) and are detectable in amniotic fluid (Huang et al. 2009, Wittassek et al. 2009). Post-natally, they can reach the newborn via breast milk (Main et al. 2006a). "
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    ABSTRACT: We hypothesised that antenatal exposure to ubiquitous phthalates may lead to an earlier menarche and a lower prevalence of polycystic ovarian syndrome (PCOS) and polycystic ovarian morphology (PCO) in adolescence. The Western Australian Pregnancy Cohort (Raine) Study recruited 3000 women at 18 weeks of gestation in 1989-91, 1377 had antenatal serum stored without thawing at -80°C. An unselected subset was evaluated in the early follicular phase for PCO and PCOS by ultrasound and serum evaluation in adolescence. Serum was analysed for Anti-Mullerian Hormone (AMH), inhibin B, sex-hormone binding globulin (SHBG), testosterone, androstenedione and DHEAS. 400 µL of the frozen maternal serum underwent isotope diluted liquid chromatography - tandem mass spectrometry (LC-MS/MS), with preceding enzymatic deconjugation followed by solid phase extraction to determine phthalate exposure. 244 girls attended assessment and most common phthalate metabolites were detectable in the majority of the 123 samples available. Several phthalates were negatively associated with maternal SHBG, associations with maternal androgens were less consistent. The sum of the metabolites of di-(2-ethylhexyl) phthalate (DEHP) were associated with a non-significant tendency towards an earlier age at menarche (p=0.069). Uterine volume was positively associated with mono-(carboxy-iso-octyl) phthalate (MCiOP) (p=0.018). Exposure to monoethyl phthalate (MEP) and the sum of all phthalate metabolites (Σall phth.m) was protective against PCOS in adolescence (p=0.001, p=0.005, respectively). There were negative associations of MEP with PCO (p=0.022), and MEP with serum AMH (p=0.031). Consequently our data suggests that antenatal exposure to environmental phthalates may be associated with oestrogenic and/or anti-androgenic reproductive effects in adolescent girls.
    Reproduction 09/2013; 147(4). DOI:10.1530/REP-13-0331 · 3.17 Impact Factor
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    • "Experimental evidence showed that oxidative DNA damage could interfere with the capability of methyltransferases to interact with DNA resulting in lower methylation of cytosine residues at CpG sites [37]. Since trophoblast differentiation is most important early in pregnancy when the placenta is initially being constructed [38] and maternal air pollution exposure may influence markers of placental growth and function [39], it could well be that altered global DNA methylation during early pregnancy influences placental development. Maternal tobacco smoke, a personalized form of air pollution, has shown to alter placental methylation levels [22,40] and underlie changes to placental function that may lead to altered fetal development and programming [22] or pregnancy pathologies such as impaired fetal growth [41] and preterm delivery [42,43]. "
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    ABSTRACT: Background There is evidence that altered DNA methylation is an important epigenetic mechanism in prenatal programming and that developmental periods are sensitive to environmental stressors. We hypothesized that exposure to fine particles (PM2.5) during pregnancy could influence DNA methylation patterns of the placenta. Methods In the ENVIRONAGE birth cohort, levels of 5’-methyl-deoxycytidine (5-mdC) and deoxycytidine (dC) were quantified in placental DNA from 240 newborns. Multiple regression models were used to study placental global DNA methylation and in utero exposure to PM2.5 over various time windows during pregnancy. Results PM2.5 exposure during pregnancy averaged (25th-75th percentile) 17.4 (15.4-19.3) μg/m3. Placental global DNA methylation was inversely associated with PM2.5 exposures during whole pregnancy and relatively decreased by 2.19% (95% confidence interval [CI]: -3.65, -0.73%, p = 0.004) for each 5 μg/m3 increase in exposure to PM2.5. In a multi-lag model in which all three trimester exposures were fitted as independent variables in the same regression model, only exposure to PM2.5 during trimester 1 was significantly associated with lower global DNA methylation (-2.13% per 5 μg/m3 increase, 95% CI: -3.71, -0.54%, p = 0.009). When we analyzed shorter time windows of exposure within trimester 1, we observed a lower placental DNA methylation at birth during all implantation stages but exposure during the implantation range (6-21d) was strongest associated (-1.08% per 5 μg/m3 increase, 95% CI: -1.80, -0.36%, p = 0.004). Conclusions We observed a lower degree of placental global DNA methylation in association with exposure to particulate air pollution in early pregnancy, including the critical stages of implantation. Future studies should elucidate genome-wide and gene-specific methylation patterns in placental tissue that could link particulate exposure during in utero life and early epigenetic modulations.
    Particle and Fibre Toxicology 06/2013; 10(1):22. DOI:10.1186/1743-8977-10-22 · 7.11 Impact Factor
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    • "Phthalates have also been shown to affect trophoblast cells in human placentae. For instance, higher maternal urinary concentrations of five phthalate metabolites (MEHP, MEOHP, MnBP, MiBO, MBzP) have been associated with a decreased expression of trophoblast differentiation markers (PPARc, AhR, hCG), leading to alterations in human placental development and function (Adibi et al., 2010). Interestingly, in rat HRP-1 trophoblast cells exposure to DEHP, MEHP and 2-ethylhexanoic acid also results in significant increases in the concentrations of different lipid classes (Xu et al., 2006), leading to the conclusion that these chemicals might affect placental and/or foetal fatty acid/lipid homeostasis and lead to abnormal foetal development. "
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