EDCs exposure linked to altered gene function in pregnant women’s placentas

Chemicals may alter placenta genes, threaten fetuses

image of a Spritz-of-Perfume
Researchers link endocrine disrupting chemical exposure to altered gene function in pregnant women’s placentas, which could hamper fetal growth. A Spritz of Perfume image by Jennuine Captures Photography.

Women exposed to widely used chemicals while pregnant are more likely to have altered gene function in their placentas, according to a new study.

2015 Study Abstract

Background:
There is increasing concern that early-life exposure to endocrine-disrupting chemicals (EDCs) can influence the risk of disease development. Phthalates and phenols are two classes of suspected EDCs that are used in a variety of everyday consumer products, including plastics, epoxy resins, and cosmetics. In utero exposure to EDCs may impact disease propensity through epigenetic mechanisms.

Objective:
The objective of this study was to determine if prenatal exposure to multiple EDCs is associated with changes in miRNA expression of human placenta, and if miRNA alterations are associated with birth outcomes.

Methods:
Our study was restricted to a total of 179 women co-enrolled in the Harvard Epigenetic Birth Cohort and the Predictors of Preeclampsia Study. We analyzed associations between first-trimester urine concentrations of 8 phenols and 11 phthalate metabolites and expression of 29 candidate miRNAs in placenta by qRT-PCR.

Results:
For three miRNAs, miR-142-3p, miR15a-5p, and miR-185, we detected associations between ∑phthalates or ∑phenols on expression levels (p<0.05). By assessing gene ontology enrichment, we determined the potential mRNA targets of these microRNAs predicted in silico were associated with several biological pathways, including the regulation of protein serine/threonine kinase activity. Four gene ontology biological processes were enriched among genes significantly correlated with the expression of miRNAs associated with EDC burden.

Conclusions:
Overall, these results suggest that prenatal phenol and phthalate exposure is associated with altered miRNA expression in placenta, suggesting a potential mechanism of EDC toxicity in humans.

Sources and more information
  • First-Trimester Urine Concentrations of Phthalate Metabolites and Phenols and Placenta miRNA Expression in a Cohort of U.S. Women, Environ Health Perspect; DOI:10.1289/ehp.1408409, 19 June 2015.
  • Chemicals may alter placenta genes, threaten fetuses, Environmental Health News, July 1, 2015.

Bisphenol A triggers Epigenetic Changes in Rats that may lead to Breast Cancer

Fetal BPA exposure triggers changes in the postnatal and adult mammary gland epigenome and alters gene expression patterns

Prenatal Exposure to BPA Alters the Epigenome of the Rat Mammary Gland and Increases the Propensity to Neoplastic Development

Abstract

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Fetal BPA exposure triggers changes in the postnatal and adult mammary gland epigenome and alters gene expression patterns.

Exposure to environmental estrogens (xenoestrogens) may play a causal role in the increased breast cancer incidence which has been observed in Europe and the US over the last 50 years. The xenoestrogen Bisphenol-A (BPA) leaches from plastic food/beverage containers and dental materials. Fetal exposure to BPA induces preneoplastic and neoplastic lesions in the adult rat mammary gland. Previous results suggest that BPA acts through the estrogen receptors which are detected exclusively in the mesenchyme during the exposure period by directly altering gene expression, leading to alterations of the reciprocal interactions between mesenchyme and epithelium. This initiates a long sequence of altered morphogenetic events leading to neoplastic transformation. Additionally, BPA induces epigenetic changes in some tissues.

To explore this mechanism in the mammary gland, Wistar-Furth rats were exposed subcutaneously via osmotic pumps to vehicle or 250 µg BPA/kg BW/day, a dose that induced ductal carcinomas in situ. Females exposed from gestational day 9 to postnatal day (PND) 1 were sacrificed at PND4, PND21 and at first estrus after PND50. Genomic DNA (gDNA) was isolated from the mammary tissue and immuno-precipitated using anti-5-methylcytosine antibodies. Detection and quantification of gDNA methylation status using the Nimblegen ChIP array revealed 7412 differentially methylated gDNA segments (out of 58207 segments), with the majority of changes occurring at PND21. Transcriptomal analysis revealed that the majority of gene expression differences between BPA- and vehicle-treated animals were observed later (PND50). BPA exposure resulted in higher levels of pro-activation histone H3K4 trimethylation at the transcriptional initiation site of the alpha-lactalbumin gene at PND4, concomitantly enhancing mRNA expression of this gene.

These results show that fetal BPA exposure triggers changes in the postnatal and adult mammary gland epigenome and alters gene expression patterns. These events may contribute to the development of pre-neoplastic and neoplastic lesions that manifest during adulthood.

Sources
  • Prenatal Exposure to BPA Alters the Epigenome of the Rat Mammary Gland and Increases the Propensity to Neoplastic Development, PLOS one, DOI: 10.1371/journal.pone.009980, July 02, 2014 – PDF.
  • BPA triggers changes in rats that may lead to breast cancer, Environmental Health News, bpa-mammary-glands, July 2, 2014

Molecular Feminization of Mouse Seminal Vesicle by Prenatal Exposure to DiEthylStilbestrol

Feminization of the male mouse reproductive tract after prenatal exposure to DES

1994 Study Abstract

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Feminization of the male mouse reproductive tract after prenatal exposure to Diethylstilbestrol.

Exposure to estrogens during critical stages of development has been reported to cause irreversible changes in estrogen target tissues such as the reproductive tract. In fact, recent studies using mice describe prenatal estrogen exposure resulting in the expression of the major estrogen-inducible uterine secretory protein, lactoferrin (LF), by the seminal vesicles of the male offspring. Thus, we have studied the role of estrogens in abnormal and normal gene expression in the developing male reproductive tract using LF and seminal vesicle secretory protein IV (SVS IV), an androgen-regulated murine seminal vesicle secretory protein, as markers. Lactoferrin and SVS IV protein and mRNA expression were studied in histological samples by using the techniques of in situ hybridization (ISH) and immunohistochemistry (IHC). Seminal vesicle secretory protein IV was expressed in all (100%) epithelial cells of the control seminal vesicle, but this protein was decreased by castration. However, LF expression was undetectable by ISH or IHC in control seminal vesicle epithelium. Lactoferrin was inducible in 2% of the seminal vesicle epithelial cells from adult castrated mice treated with estradiol 17 beta (E2; 20 micrograms/kg/day for 3 days), indicating that a small percentage of the seminal vesicle cells could be induced to secrete LF after modification of the endocrine environment. Prenatal DES treatment (100 micrograms./kg. maternal body weight on days 9 through 16 of gestation) resulted in the male offspring exhibiting constitutive expression of LF in 5% of the seminal vesicle epithelial cells, while expression of the androgen-regulated protein SVS IV was slightly decreased. The maximal contrast between LF and SVS IV expression was observed in prenatally DES-treated mice that were subsequently castrated as adults and further treated with E2; LF was detected in 40% of the epithelial cells in these mice. Double immunostaining techniques revealed that epithelial cells which were making LF had ceased production of SVS IV. Since a large percentage of the epithelial cells in the intact prenatal DES exposed male was capable of expressing the normal gene product, SVS IV, it was concluded that DES treatment during prenatal development appears to imprint or induce estrogenic sensitivity in the adult seminal vesicle, causing increased production of LF. The results suggest that this altered protein response may be an example of atypical gene expression in male reproductive tract tissues following hormonal manipulation early in development.

Sources:
  • Molecular feminization of mouse seminal vesicle by prenatal exposure to diethylstilbestrol: altered expression of messenger RNA, NCBI, PMID: 8158792, 1994 May;151(5):1370-8.
More DES DiEthylStilbestrol Resources

Female Gene Expression in the Seminal Vesicle of Mice after Prenatal Exposure to Diethylstilbestrol

The seminal vesicle of prenatally DES-exposed male mice acquired two key characteristics of female tissues

Abstract

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The seminal vesicle of prenatally DES-exposed male mice has acquired two key characteristics of female tissues.

Previous studies from our laboratory on the feminization of the male mouse reproductive tract after prenatal exposure to Diethylstilbestrol (DES) showed that the mRNA for the major estrogen-inducible uterine secretory protein, lactoferrin (LF), was constitutively expressed in the seminal vesicle of male mice exposed prenatally to DES, but not in the seminal vesicle of control mice. After castration, treatment with 17 beta-estradiol (20 micrograms/kg.day) for 3 days induced the LF mRNA in the seminal vesicle of both control and prenatally DES-exposed mice; however, the levels in DES-treated tissues were approximately 6-fold higher than those in control tissue. This report describes the presence of LF in seminal vesicle tissues and secretions of prenatally DES-exposed mice, as determined by immunohistochemistry and Western blot analysis. Further, these data are correlated with immunolocalization of the estrogen receptor in the seminal vesicle tissue. We conclude that the seminal vesicle of prenatally DES-exposed male mice has acquired two key characteristics of female tissues, namely LF production/regulation and estrogen receptor localization/distribution similar to that in uterine tissues.

Sources:
  • Female gene expression in the seminal vesicle of mice after prenatal exposure to diethylstilbestrol, NCBI, PMID: 2707167, 1989 May;124(5):2568-76.
More DES DiEthylStilbestrol Resources