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Prenatal exposure of xenoestrogens and repetitive element DNA methylation changes in human placenta

Study published in Environmental International and leaded by CREAL

Wednesday, September 3th, 2014

Prenatal exposure of xenoestrogens and repetitive element DNA methylation changes in human placenta

In a study published in Environmental International and leaded by Nadia Vilahur PhD, researcher at CREAL, an ISGlobal research centre, in collaboration with Harvard University, the researchers measured in more than 180 placenta samples from the prospective cohort study INMA the Total Effective Xenoestrogenic Burden (TEXB-alpha), a biomarker evaluating the total estrogenicity due to exogenous lipophilic xenoestrogens found in placenta. The findings suggest that boys may be more susceptible to the effect of exposure to xenoestrogens during prenatal development, producing shifts in DNA methylation of certain sensitive genomic repetitive sequences in a tissue important for fetal growth and development.

Endocrine Disrupting Chemicals are molecules that are able to interact with the endocrine system of different species, including humans, leading to hormonal dysregulation and potentially be involved in the occurrence of diseases that are increasing in prevalence such as cancer, childhood obesity, fertility problems and neurobehavioral abnormalities. These chemicals are of special concern if exposure occurs during susceptible developmental windows to the effects of hormones like the prenatal period.

Xenoestrogens are a group of Endocrine Disrupting Chemicals that interfere with the estrogenic signaling pathways, and include a large number of molecules present in pesticides, in the manufacture of materials, and goods like resins, textiles, plastics, cosmetics, flame retardants or insulators among other uses. They are ubiquitously present in the environment in complex mixtures and can cross the placental barrier from the maternal side due to their small size and often lipophilic properties. As a result of prenatal exposure to xenoestrogenic chemicals, the placental epigenome may be deregulated, leading to changes in placental gene regulation and/or increased genomic instability, with putative adverse effects on fetal development and health.

In addition, global DNA methylation in the same tissue was assessed by bisulfite pyrosequencing of ten different types of DNA sequences called retrotransposons (LINEs, Alus and HERV). These are highly repetitive DNA sequences that account for up to half of the entire human genome and have been used as a proxy to study genomic global DNA methylation. Several retrotransposons have the ability to propagate themselves through RNA-mediated mechanisms and may produce insertional mutations or deregulate gene expression. Hypomethylation of retrotransposons has been attributed to increased genomic instability and has been commonly observed in complex disorders such as cancer.

“We found that higher levels of placental TEXB-alpha exposure where associated with a significant 0.84% decrease in the methylation levels of an Alu element only in boys, while no effects were observed in girls”, explained Vilahur. Although statistically non-significant after multiple testing correction, a trend towards hypomethylation was also observed in two LINE elements also only in boys.

The results suggest that early xenoestrogen exposure may lead to sex-specific epigenomic deregulation in placenta so that males present increased vulnerability. “Studies on Endocrine Disrupting Chemicals should take into account sex as an important effect modifier in relation to early hormonal-related exposures”, concluded Vilahur.

More information: Environ Int. Epub 2014 Jun 28. Prenatal exposure to mixtures of xenoestrogens and repetitive element DNA methylation changes in human placenta. Vilahur N et al.


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