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Maternal Transcriptomic Regulation of the Preimplantation Embryo

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ClinicalTrials.gov Identifier: NCT02813746
Recruitment Status : Unknown
Verified June 2016 by Carlos Simon, Igenomix.
Recruitment status was:  Recruiting
First Posted : June 27, 2016
Last Update Posted : June 28, 2016
Sponsor:
Information provided by (Responsible Party):
Carlos Simon, Igenomix

Brief Summary:

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


Condition or disease Intervention/treatment
Fetal Origin of Adult Diseases Dietary Supplement: Fitness program Behavioral: Stop smoking Procedure: Endometrial fluid collection

Detailed Description:

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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Study Type : Observational
Estimated Enrollment : 90 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Maternal Transcriptomic Regulation of the Preimplantation Embryo
Study Start Date : April 2016
Estimated Primary Completion Date : April 2017
Estimated Study Completion Date : April 2019

Group/Cohort Intervention/treatment
Obese non smoker vs Normoweight non smoker
Endometrial fluid (EF) will be obtained from non-smokers normo-weight and obese patients in the receptive state. Samples will be collected 7 days after Luteinizing Hormone (LH) peak. They will be classified following the guidelines of the obesity classification system by the World Human Organization (WHO). Patients will be subjected to a fitness program during a year with the aim to achieve a weight reduction to normal values (19-24.9 kg/m2). The modifications in the miRNAs expression will be studied. After the weight loss, new EF will be collected from these patients.
Dietary Supplement: Fitness program
Procedure: Endometrial fluid collection
Normoweight smoker vs Normoweight non-smoker
EF will be obtained from non-smokers and smokers normo-weight in the receptive state. Samples will be collected 7 days after Luteinizing Hormone (LH) peak. Smokers patients will be urge to give up smoking during at least one year. After this time, new samples will be collected to determine if the non-exposition to this contaminant could exert any effect in the miRNAs signature. A regular control will be done in this group of patients to ensure that they have not been exposed to tobacco in 12 months. Professional support will be given in the same centre of the study to help the patient to accomplish its objective.
Behavioral: Stop smoking
Procedure: Endometrial fluid collection



Primary Outcome Measures :
  1. Understanding of the epigenetic and transcriptomic mechanisms that regulate the FOAD [ Time Frame: 40 months ]
    The main objective of the present project is focused on understanding the epigenetic and transcriptomic mechanisms that regulate the fetal origin of adult diseases (FOAD) either by the presence of metabolic disorders in mothers such as obesity, or by the exposure to certain pollutants such as tobacco


Secondary Outcome Measures :
  1. Analysis of the miRNA expression pattern in the endometrial fluid (EF) in obese patients Analysis of the miRNA expression profile in the endometrial fluid [ Time Frame: 13 months ]
    miRNA expression profile will be analysed in obese women , in comparison to normoweight women during the window of implantation. In turn, the normalization of this particular transcriptomic signature will be studied after the existence of a substantial loss of weight by the patients involved in the study.

  2. Analysis of the miRNA expression pattern in the endometrial fluid (EF) in smoker patients [ Time Frame: 13 months ]
    A comparison between the miRNA expression profiles in smoker women vs. non-smoker will be done in the endometrial fluid (EF) during the window of implantation. As in the previous case, it will be studied if that particular pattern is normalized after giving up smoking.

  3. Functional analysis [ Time Frame: 13 months ]
    The target genes and the metabolic routes affected by the miRNA profile secreted in both pathological conditions will be defined.


Biospecimen Retention:   Samples With DNA
DNA will be analyzed in the endometrial fluid. These samples will be completely exhausted during the analysis.


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Endometrial fluids from non-smoker obese and normoweight samples will be analysed in the window of implantation. In turn, endometrial fluids from normoweight smoker and non-smoker patients will be analysed in the window of implantation.

These participants will be recruited in just one centre: IVI Valencia. Their recruitment will be done through a routine consultation carried out by the research team from the centre, as well as through the revision and daily evaluation of the medical reports and subsequent contact with those patients who could accomplish with the criteria selection and desire to be involved in the study.

Criteria

Inclusion Criteria:

  • Women with age comprised between 18 and 45 years
  • Normal uterus (evaluated trough ultrasound 2D/3D and/or hysteroscopy)
  • Presence of at least one ovary
  • Body mass index:
  • Normoweight: 18.0-24.9 kg/m2 and non smokers
  • Obese ≥30.0 kg/m2 and non smokers
  • Smokers: Normoweight and smoke at least 10 cigarettes per day

Exclusion Criteria:

  • Overweight=25.0-29.9 kg/m2
  • Patients with Intrauterine device in the last 3 months
  • Patients who had had hormonal contraceptives in the 2 previous months.
  • Adnexal or uterine pathologies
  • Polycystic ovary
  • Existence of serious or uncontrolled bacterial, fungal or viral infections that could interfere with the involvement of the patient in the study or in the evaluation of the study results.
  • Any disease or medical condition that could be unstable or could endanger the security of the patient and her compliance in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02813746


Contacts
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Contact: Carlos Gomez, BSc MSc +34963905310 carlos.gomez@igenomix.es
Contact: Diana Valbuena, MD PhD +34963905310 diana.valbuena@igenomix.es

Locations
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Spain
IVI Valencia Recruiting
Valencia, Spain, 46015
Contact: Carlos Simon, MD PhD    +34963050900    carlos.simon@ivi.es   
Sponsors and Collaborators
Igenomix
Investigators
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Principal Investigator: Carlos Simón, MD PhD Igenomix
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Responsible Party: Carlos Simon, Scientific Director IGENOMIX; Gynaecologist IVI Valencia, Igenomix
ClinicalTrials.gov Identifier: NCT02813746    
Other Study ID Numbers: 1603-IGX-018-CS
First Posted: June 27, 2016    Key Record Dates
Last Update Posted: June 28, 2016
Last Verified: June 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Carlos Simon, Igenomix:
Obesity
Tobacco
Epigenetic
Transcriptomic
microRNAs
miRNAs