Infertil-SaFe: An integrative and multiscale study to identify the determinants and mechanisms of infertility and improve assisted reproductive technologies

Program presentation

Infertility, the inability to obtain a pregnancy followed by a living birth despite at least 12 months of unprotected sexual intercourse, affects 3.3 million people in France.

Multiple factors cause this increased infertility including the increased age at childbearing, medical causes  and environmental and lifestyle factors.

Among the medical causes, polycystic ovary syndrome affecting up to 13% of women of reproductive age, and primary ovarian insufficiency (premature cessation of ovarian function) affecting 1-3% of women under 40, represent major causes of infertility. The genetic and environmental determinants of these reproductive diseases still need to be fully understood as for severe sperm defects, which have widely progressed in the last decades. Some of the environmental and lifestyle factors incriminated in fertility decline include exposure to endocrine disrupting chemicals, global warming and occurrence of heat stress episodes, diet and rising rates of obesity, stress…

In this context of increased infertility, the demand in assisted reproduction has been steadily increasing for the last decades. In France, assisted reproductive techniques contributed to the birth of over 400 000 babies since the 1980s. Nevertheless, the success rate of assisted reproduction remains low, which is painful and stressful for women and couples trying to conceive.

There is therefore an urgent need to improve reproductive health and make assisted reproductive techniques more successful and efficient. For this purpose, our Infertil-SaFe research program, carried by the “Women’s and Couples’ Health” Research Program (PEPR SAFE), tackles three main complementary objectives.

Objectives
    • Characterize the impact and mechanisms of environmental and lifestyle factors on reproductive health and identify early predictive biomarkers
    • Progress in the understanding of the mechanisms underlying the pathophysiology of infertility and exploring possible therapeutic leads
    • Advance the comprehension of gametogenesis, early embryo development and the interaction between the embryo and the endometrium to radically improve assisted reproduction and fertility preservation
Detailed program

The Infertil-SaFe program focuses on 3 main research axes:

    1. Environmental and lifestyle impact, and predictive biomarkers
    2. Integrated pathophysiology of infertility
    3. Improving assisted reproductive technologies from gametes to implantation

Objectives: Study the role of environmental exposures and lifestyle habits int the etiology of infertility, their relations with fertility management and generate appropriate guidelines for prevention diagnosis and early risk prediction.

Leaders: Ronan Garlantézec & Pascale Chavatte-Palmer

1.1. Characterize the impact of environmental exposure and lifestyle factors on reproductive outcomes

Objective: Assess the association between exposure to a large set of environmental factors, lifestyle factors and reproductive health, understand the relations between these factors and female, male and idiopathic infertility, and understand how such factors influence reproductive outcomes and the success of fertility preservation and assisted reproductive techniques.

Leaders: Ronan Garlantezec/Charline Warembourg, Rachel Levy & Mathilde Bourdon

1.2. Characterize the mechanisms underlying the effects of environmental exposure and lifestyle factors on reproductive outcomes

Objective: Explore the mechanisms leading to impaired fertility after developmental exposure to environmental and lifestyle factors reported or suspected to affect offspring fertility in humans, by identifying relevant chemical mixtures in existing mother-child cohorts and proceeding to physiological and functional studies (neuroendocrine and behavioral effects, mechanisms of exposure, epigenetic).

Leaders: Reiner Veitia, Sakina Mhaouty-Kodja, Ghyselinck Norbert, Ronan Garlantezec/Charline Warembourg, Anu Bashamboo, Pascale Chavatte-Palmer, Jérôme Jullien & Samir Hamamah

1.3. Identify predictive biomarkers and models in human

Objective: Develop predictive models and tools that improve fertility outcomes and support the prevention of infertility by 1) identifying individuals at higher risk for infertility, allowing for early intervention and personalized fertility management, and 2) enhancing patient education, optimize fertility preservation techniques, and ultimately improve reproductive care through innovative approaches.

Leaders: Sakina Mhaouty-Kodja & Rachel Levy

Objectives: Unravel the complex mechanisms underlying male and female infertility through an in-depth exploration of i) neuroendocrine, ovarian and testicular dysfunction, and ii) underlying molecular processes governing gametogenesis at the genetic, epigenetic and endocrine levels. The third aim of this study is to develop diagnostic tools and therapeutic strategies to enhance gamete quality and improve fertility.

Leaders: Paolo Giacobini, Nathalie Rives & Reiner Veitia

2.1. Characterize the pathophysiology of male and female Infertility at the neuroendocrine level

Objective: Generate a transcriptomic and epigenomic cell atlas underlying polycystic ovary syndrome transmission and perpetuation, and develop human in vitro models to analyze the hypothalamus-pituitary integrity.

Leaders: Paolo Giacobini & Sakina Mhaouty-Kodja

2.2. Identify new genes and pathways involved in the pathophysiology of Infertility at the gonadal level

Objective: Perform a precise phenotypic characterization and build a biobank with relevant and accessible samples to identify and study candidate genes.

Leaders: Reiner Veitia, Pierre Ray & Anu Bashamboo

2.3. Functional analysis of key regulators of female and male gametogenesis

Objective: Focus on pivotal genes and pathways known to be crucial for female and male gametogenesis, such as FOXL2, LH/FSH and ATRA signaling.

Leaders: Reiner Veitia, Pierre Ray, Anu Bashamboo, Éric Reiter & Norbert Ghyselinck

2.4. Develop potential therapeutic interventions to restore and improve gonadal function

Objective: 1) Synthesize a novel TET-1 inhibitor (nanobody with blocking-function activity) and test its therapeutic potential in polycystic ovary syndrome-like animals, 2) Deliver preclinical proof of concept for VHH-derived biologicals endowed of agonistic, antagonistic or allosteric properties, 3) Study the impact of isotretinoin (acne treatment shown to increase sperm production) administration on a large cohort of oligospermic infertile patients, 4) Create the first single-cell molecular reference roadmap of immature testicular tissue and explore disturbed signaling pathways induced by chemotherapy after in vitro maturation, 5) Optimize mRNA delivery, stability and efficiency of transcription of spermatogenesis-critical genes to restore functional spermatogenesis.

Leaders: Paolo Giacobini, Éric Reiter, Norbert Ghyselinck, Nathalie Rives & Pierre Ray

Objectives: Establish new markers, non-invasive diagnostics, as well as new therapeutic strategies to improve assisted reproductive technology and fertility by characterizing relevant biological materials and developing stem-cell based models to functionally validate observations gathered on human embryos.

Leaders: Patricia Fauque & Jean-Léon Maître

3.1. Interdisciplinary characterization of gametes

Objective:Extensively characterize gametes, especially oocytes mechanical properties and sperm epigenome, by combining cutting edge genetic, epigenetic, biochemical, cellular and biophysical techniques.

Leaders: Mathilde Bourdon, Patricia Fauque, Jean-Léon Maître, Marie-Émilie Terret, Katja Wassmann, Pierre Ray & Jérôme Jullien

3.2. Interdisciplinary characterization of preimplantation embryos

Objective: Improve the assessment of embryo quality to increase the success rate of implantation and pregnancy after embryo transfer by 1) integrating multiple data sources to gain insight on human preimplantation development and 2) developing new methods to comprehensively study preimplantation development.

Leaders: Patricia Fauque, Thomas Freour, Hervé Turlier, Pierre Ray, Jean-Léon Maître, Claire Rougeulle, Laurent David & Marie-Émilie Terret

3.3. Peri-implantation embryos and implantation

Objective: Obtain a comprehensive understanding of the factors that influence successful embryo implantation, focusing on both the embryonic part, including its sex, and the endometrial receptivity, including its immuno-microbiological state.

Leaders: Patricia Fauque, Jean-Léon Maître, Laurent David, Édouard Lecarpentier & Claire Rougeulle

Infertility Consortium Teams