Fetal Origin of Adult Diseases Clinical Trial
Official title:
Maternal Transcriptomic Regulation of the Preimplantation Embryo
The aim of this study is to understand the epigenetic and transcriptomic mechanisms that
regulate the fetal origin of adult diseases (FOAD), either for the presence of metabolic
disorders in the future mothers, such as obesity or for the exposure to certain contaminants
such as tobacco.
To do that, the miRNAs profiles secreted to the endometrial fluid in obese women vs
normoweight women during the window of implantation will be identified. Likewise, it will be
studied how that miRNA signature is normalized once a substantial loss of weight is produced
by the patients involved in the studied. In parallel, a comparison of the miRNA expression
profiles secreted in the endometrial fluid in smoker women vs nonsmoker women will be
performed. As in the previous case, it will be studied if after the exposure to these
contaminant, the normalization of the miRNA expression signature occurs. Finally, an in
silico analysis will be carried out in order to define the target genes and the metabolic
pathways affected by the miRNAs profile secreted in both pathological conditions
The developmental origins of adult disease are now recognized to be related to intrauterine
conditions during embryonic and fetal life. Pregnancy begins with embryo implantation and
its impact in adult life remains unknown. It has been demonstrated that human endometrial
epithelium secretes specific microRNAs (miRNAs) during the time frame when the embryo enters
the uterine cavity and initiates its adhesion to the uterine wall. Maternal miRNAs are
secreted to the endometrial fluid, transported through exosomes or bound to proteins and
consequently uptaken by the preimplantation embryo, before implantation occurs. As a
consequence they suffer transcriptomic modifications that induce profound molecular and
functional changes. The data already published demonstrate a novel paradigm: the
transcriptomic maternal endometrial regulation of the pre-implantation embryo in health.
Here, this novel maternal endometrium-based mechanism will be applied in order to understand
and prevent the developmental origin of adult diseases induced during embryonic implantation
either by metabolic disorders of future mothers who have developed obesity or by the
exposure to certain contaminants such as tobacco. In this project, the expression profiles
of secreted miRNAs will be identified in the endometrial fluid in obese women compared to
normo-weight women. Also, it will be studied how this "obese" endometrial miRNA pattern is
reversed after weight-loss. In parallel, murine models of obesity will be used to proof this
concept. In addition, the expression profiles of secreted endometrial miRNAs will be
identified in smokers versus future non-smokers mothers. As in the previous case, the
reversion of this signature will be analysed after stopping the exposure to this
contaminant.
Then, "in silico" analysis will be done to select putative genes and functional pathways
targeted by the signature of secreted endometrial miRNAs in the human and murine models in
both pathological conditions. The determination of the transcriptomic and/or epigenome
modifications induced by "obese" or/and "smoker" endometrial miRNAs in preimplantation mouse
embryos is expected. As preliminary results, to support this project our accepted model of
transcriptomic maternal endometrial regulation of the pre-implantation embryo in health, and
the identification of a differential pattern of secreted miRNAs in the endometrial fluid of
obese women compared to normo-weight counterparts is presented. In consequence, the
application of this novel endometrium-based mechanism to the understanding and prevention of
the origin of adult diseases related to obesity and/or tobacco exposure is proposed.
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Observational Model: Cohort, Time Perspective: Prospective