Research Jo Leroy

Abstract

Background: The exposome encompasses the totality of environmental exposures of an individual or organism throughout life (including exposure to chemicals, diet, lifestyle, climate factors, stress), and how these exposures impact biology (e.g., metabolites, hormones, etc.) and health. In particular, exposure to endocrine disrupting chemicals (EDCs), including metabolic disrupting chemicals (MDCs), has been linked to a broad range of non-communicable diseases and environmental health effects. Workflows for gathering and interpreting exposome data are still in development and are currently focusing on elucidating physiological pathways that link exposure to adverse effects. Ultimately, this will lead to a holistic understanding of how exposures interact with the phenotype to cause adverse health outcomes with potentially large societal, economic, and ecological costs. Aims: We will use innovative approaches to decipher the human exposome from early life on up to adulthood and its association with endocrine and metabolic alterations (leading to disorders, such as liver diseases, metabolic syndrome, diabetes, and obesity), as well as effects on other important physiological processes mostly driven by endocrine and metabolic signaling.

Researcher(s)

• Promoter: Covaci Adrian
• Co-promoter: Bervoets Lieven
• Co-promoter: Bittremieux Wout
• Co-promoter: De Boeck Gudrun
• Co-promoter: Hermans Nina
• Co-promoter: Jorens Philippe
• Co-promoter: Knapen Dries
• Co-promoter: Leroy Jo
• Co-promoter: van Nuijs Alexander

Research team(s)

• Toxicological Centre

Project type(s)

• Research Project

Abstract

Antibodies (Abs) have a proven track record in biotechnology and -medicine. Most applications are based on conventional Abs (mostly IgGs), which have constituted a highly profitable market for decades. However, despite their track record, conventional Abs have their drawbacks and are ill-suited for certain applications. These shortcomings can usually be overcome by unconventional Abs found in other mammals. A prime example is provided by the Belgian discovery of a peculiar Ab subset that naturally occurs in camelids (e.g., camels, dromedaries, and llamas). In these Abs, antigen recognition is mediated by a single domain, which is why this domain is often referred to as a "single-domain antibody" (sdAb aka nanobody®). Camelid sdAbs possess unique features that are not usually found in conventional Abs: a small size (~15 kDa), an increased solubility, robust folding properties, a high intrinsic stability, poor immunogenicity, and the relative ease to tailor them (modifications according to a "plug-and-play" principle). These remarkable properties render them highly suitable for discovery, application, and valorisation in life sciences (including diagnostics and therapeutics). Importantly, the number of sdAbs in clinical trials and approved by the relevant regulatory agencies is on the rise (sdAbs are catching up with conventional Abs): in the past five years, four sdAbs have been approved for clinical use, ~50 others are currently in clinical trials, and many patents have been submitted/granted around the world. sdAbs are readily obtained through camelid immunisation or in silico designed synthetic sdAb libraries that have been shown to perform equally well. Immune and synthetic sdAb libraries each have their strengths and drawbacks and therefore complement each other. In most cases, interested parties have access to either immune or synthetic libraries but very rarely to both. Clearly, access to both library types through a hybrid platform will create a powerful synergy that can fuel discovery, innovation, and valorisation. The unique selling proposition of this project is the establishment of HyCAbs, an in-house hybrid sdAb platform based on the combined strengths of immune and synthetic libraries that can be employed to swiftly identify sdAbs against a myriad of target antigens. HyCAbs represents a continuation of the previously awarded PREPARAS project (Antigoon ID 49344). With this IOF PoC CREATE proposal, we aspire to consolidate and open this initiative up to i) UAntwerp researchers active in other life science domains and ii) interested external parties (both academic and industrial). In addition, we aim to unleash the potential of machine learning on deep sequencing data obtained from camelids to design and construct next-generation synthetic sdAb libraries by marrying our in-house sdAb expertise with the know-how of the BIOMINA core facility. The hybrid nature of HyCAbs is unique. One of its features would be to offer the interested party full flexibility in acquiring sdAbs through camelid immunisation, screening against synthetic libraries, or both. This flexibility enables the simultaneous consideration of sample amounts, time from antigen provision to binder identification, and budgetary constraints. For UAntwerp researchers, HyCAbs offers relatively cheap sdAb access with in-house IP from the start, which will add value for the university. For external parties, service agreements will be negotiated. Hence, we expect HyCAbs to provide various valorisation routes. HyCAbs presents a unique opportunity to establish a robust sdAb platform that enables discovery, innovation, and valorisation in its current form and supports low risk expansion and implementation of innovative elements in the field of sdAb technology in the future.

Researcher(s)

• Promoter: Sterckx Yann
• Co-promoter: Caljon Guy
• Co-promoter: Leroy Jo

Research team(s)

• Medical Biochemistry

Project type(s)

• Research Project

Abstract

Obesity is a global threat that not only affects women's fertility but also endangers the health of the offspring. The developmental capacity of oocytes under metabolic stress, associated with obesity, is decreased due to higher levels of oxidative stress (OS) and mitochondrial (MT) dysfunction. Inheritance of such defective oocyte mitochondria compromises epigenetic programming, development and postnatal health. Early embryos cannot activate the processes of mitophagy (removal of dysfunctional mitochondria) and mitogenesis (synthesis of new mitochondria), which are crucial for rejuvenating mitochondrial functions and supporting embryo survival. While current clinical preconception care interventions, such as diet normalization, improve systemic metabolic health, mitochondrial abnormalities in the oocyte persist. MT-targeted antioxidants and mitophagy-inducing substances are proven to be effective in enhancing somatic cell mitochondrial function and metabolic health. However, the potential of these compounds in oocyte-targeted preconception care strategies has never been explored. Using an outbred mouse model, this project will specifically focus on oocyte mitochondria as the key to improve female gamete quality under maternal metabolic stress conditions. The research will combine functional and molecular assessments to generate a clear understanding of the effects of MitoQ, Liraglutide and Rapamycin on oocyte and embryo quality, epigenetic programming and offspring health.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: De Neubourg Diane
• Co-promoter: Marei Waleed
• Co-promoter: Martinet Wim
• Fellow: Loier Lien

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

Obesity is becoming a global threat, not only reducing female fertility but also affecting the offspring's health. The quality of the oocytes developing under obesity-associated metabolic stress is significantly deteriorated, mainly due to oxidative stress (OS) and mitochondrial (MT) dysfunction. The defective mitochondria are transferred to the embryo, with persistently high OS levels, leading to transcriptomic, epigenetic and phenotypic alterations, and low pregnancy rates, even when clinical assisted reproductive treatments are used. Early embryos lack the machinery to re-establish cellular homeostasis or activate mitophagy and mitogenesis to rejuvenate MT functions and support embryo survival. Current clinical interventions during the preconception period, such as diet caloric normalization or restriction, have been shown to restore systemic metabolic health but fail to rescue oocyte MT functions. Emerging MT-targeted antioxidants and compounds inducing mitophagy have been proven efficient in combating MT dysfunction in several metabolic diseases. These treatments could enhance oocyte quality when supplemented in vitro, however their efficiency to enhance MT functions in metabolically stressed oocytes from obese females in vivo has not been previously investigated, yet very topical and important. In this project we hypothesize that treatments with pharmaceutical compounds can specifically support MT functions in oocytes. A targeted reduction of MT oxidative stress or activation of mitophagy and mitogenesis during the preconception period in obese females can improve oocyte quality and oocyte developmental competence. We believe that this approach will also improve embryo quality and normalize epigenetic programming during subsequent development resulting in better offspring health. Therefore, we firstly aim to enhance oocyte MT functions and quality in vivo in obese females using MitoQ, a MT targeted antioxidant (i.e. for MT TARGETED SUPPORT), or Liraglutide, a potent anti-diabetic medication increasingly used for weight management, known to stimulate mitophagy via SIRT1-PINK1-Parkin dependent ubiquitin pathway (i.e. for REPAIR and REJUVINATION). We will use a validated outbred Swiss mouse model to increase the pathophysiological relevance to the humans. Secondly, we aim to test and compare the efficiency of different MT-targeted therapies when supplemented in vitro during culture of embryos derived from mature oocytes collected from obese mice (EMBRYO RESCUE). We will compare the effects of MitoQ, Liraglutide, as well as Rapamycin to induce mitophagy by inhibiting the mTOR-TORC1 pathways. In addition, we will examine if the MT therapy could alleviate obesity-induced epigenetic alterations in the produced embryos. Lastly and most importantly, we are also planning to follow up the effect of the treatments on offspring health after embryo transfer, an insight which is lacking in the majority of studies in this field. Taken the pandemic burden of obesity and metabolic disorders, this fundamental insight is needed as a basis to develop efficient strategies to improve human fertility at the time of conception by targeting oocyte mitochondria. We furthermore need this evidence-based proof of concept to prioritize the health outcomes in the children born from obese mothers. The project benefits from the combined expertise of the research team at the Gamete Research centre, lead by Prof. Jo Leroy, as well as the expertise in autophagy screening and targeting provided by Prof. Wim Martinet (Laboratory of Physiopharmacology).

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: Marei Waleed
• Co-promoter: Martinet Wim
• Fellow: Loier Lien

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

Infectious disease research (including diagnostic, preventative and therapeutic development) has been a longstanding spearhead initiative of the University of Antwerp. This is driven by a vibrant research community, which is embedded in a larger "infectious disease ecosystem" in Flanders. A significant portion of these efforts is specifically devoted towards tackling protozoan parasites, a group of unicellular eukaryotes that affect the livelihoods of billions of people and their livestock around the world. Protozoan parasites cause some of the most daunting infectious diseases to have burdened humankind in past and present times (e.g., malaria, leishmaniasis, trypanosomiasis). These diseases are hallmarked by a significant mortality and a high morbidity, thereby severely impacting the quality of life and socio-economic status of those affected. Protozoan parasites are currently endemic in large parts of the world (over 100 countries ranging from the Americas to Southeast Asia) and pose a global risk due to human migration, climate change and an expanded distribution of the insect vectors that enable parasite transmission. Consequently, even currently unaffected areas (including the Western world) are confronted with disease (re-)emergence. Hence, the current burden and pandemic potential of protozoan parasites advocate the urgency and necessity to invest in tools that enable swift parasite detection and control. Some of the most potent and promising tools employed by humans in the battle against their pathogens are obtained from other animal species. A striking example is provided by the Belgian discovery of a peculiar antibody subset that naturally occurs in camelids (e.g., alpacas, llamas, camels, and dromedaries). In these antibodies, antigen recognition is mediated by a single domain, which is why it is often referred to as a "single-domain antibody" (sdAb). During the past decades it has been recognised that sdAbs possess many remarkable properties that render them highly suitable for discovery, application, and valorisation in life sciences (including diagnostics and therapeutics). These very same properties also make them unique and potent tools for pandemic preparedness and responsiveness. Literature and market analyses reveal that sdAbs remain largely under-utilised in the battle against protozoan parasites. Consequently, the application of sdAbs in the field of human and veterinary parasitology represents uncharted territory. This project aims to harness the highly complementary expertise at UAntwerp with regards to the generation and application of sdAbs in the field of parasitology to establish PREPARAS, a hybrid platform for the generation and identification of anti-parasite sdAbs via both immune and synthetic libraries. This will generate a fruitful synergy between research, application development, and valorisation given i) the veterinary expertise and strong research focus of the participating laboratories on protozoan parasite biology, ii) the unique opportunity of exploiting a hybrid platform for sdAb generation, and iii) the potential of sdAbs to address scientifical, medical and market-driven needs. Hence, PREPARAS will provide in-house access to unique research and development tools to remain at the forefront in the global battle against protozoan parasites of human and veterinary importance.

Researcher(s)

• Promoter: Sterckx Yann
• Co-promoter: Caljon Guy
• Co-promoter: Leroy Jo

Research team(s)

• Medical Biochemistry

Project type(s)

• Research Project

Abstract

The Center for Proteomics was founded about a decade ago as a UAntwerpen/VITO state-of-the-art mass spectrometry platform as a continuation of the former UAntwerpen CeProMa Core facility. Since 2017, the main focus of the UAntwerpen/VITO team was the use of proteomic approaches to identify biomarkers for early diagnosis of disease. Over the years, we have built up a multi-disciplinary team of lab technicians, mass spectrometry experts, biologists, biochemists, (bio)medical experts, mathematicians and (bio)-informaticians to set up good experimental designs, develop quality control tools, develop additional data analysis software, … Moreover, the close interactions we now have with clinical and academic partners (with complementary expertise and biobanks) give us access to high quality clinical samples and medical expertise. Today, we have the team's expertise, the network and the infrastructure that will help us bridge the gap between discovery, translation and clinical applications. Mass spectrometry based proteomics of biofluids and tissues is complementary to other techniques that are currently available at UAntwerpen. It has the advantage that it can detect modifications and discern various proteoforms. This is not possible with PCR based techniques and even new and promising techniques like single molecule protein sequencing have limitations compared to MS based techniques. Therefore, we make a combination of these techniques in our aim to create an as complete and accurate proteome profile as possible for (bio)medical applications. Besides proteomics, we also specialize in peptidomics, covering the analysis of naturally occurring small peptides which play important regulatory roles in all multicellular organisms and is especially relevant to study cellular interactions of the immune system. This type of analysis requires specialized technological skills, especially in terms of sample preparation, analytical techniques and data analysis. Some team members are worldwide pioneers in this field. This is the reason why several companies (J&J, MyNeo, …) collaborate with the CfP for exactly this type of expert scientific support. Thanks to investments from VITO and UAntwerpen (Hercules) we are equipped with state-of-the art mass spectrometers and hyphenated equipment that rival the best proteomics centers in Europe. Ours Tims-Tof mass spectrometer and Rapiflex maldi imager are unique in Flanders. With this proteomics and peptidomics platform, we focus on application driven research making it possible to work closer with the market than typical academic research groups do. This is a clear added value for both our University, VITO and the industrial partners.

Researcher(s)

• Promoter: Mertens Inge
• Co-promoter: Lemière Filip
• Co-promoter: Leroy Jo
• Co-promoter: Peeters Marc
• Co-promoter: Vanden Berghe Wim
• Co-promoter: Van Passel Steven

Research team(s)

• Center for Oncological Research (CORE)

Project website

Project type(s)

• Research Project

Abstract

Maternal metabolic disorders, e.g. obesity, affect millions worldwide and are known to cause subfertility. Altered ovarian micro-environment and the direct impact on oocyte quality is a key factor in this pathogenesis. The oocyte undergoes dynamic epigenetic reprogramming during normal follicular development. Timely acquisition of epigenetic modifications is critical for genomic imprinting and regulation of transcription during subsequent development. Dysregulated oocytes carry persistent epigenetic defects that harm offspring health. Recent insights from somatic cells and cancer biology show that mitochondria are the machinery by which metabolic changes can translate into epigenetic (dys)regulation. This is due to altered bioenergetics or changed availability of intermediate products needed for the establishment of epigenetic marks. We learned that mitochondrial dysfunction is a main cause of reduced oocyte quality under metabolic stress. Fundamental understanding of the mitochondrial-nuclear communication in growing oocytes is lacking but crucial for the development of efficient interventions to improve oocyte quality and fertility and for the protection of embryo quality and offspring health. We aim to examine the direct link between mitochondrial dysfunction in growing oocytes and epigenetic alterations, to study if these alterations are preventable or reversible using mitochondrial targeted treatments, and to test the impact of these treatments on the offspring's health.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: Marei Waleed
• Fellow: Meulders Ben

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

Mitochondria are the driving force behind virtually all vital cellular processes, including cellular proliferation, differentiation, cell death and epigenetic regulation. Consequently, their dysfunction is intricately connected to altered metabolic states and disease progression. We aim at acquiring a Seahorse XFp Analyzer, which can directly measure mitochondrial respiration and glycolysis through Oxygen Consumption Rate (OCR) and Extracellular Acidification Rate (ECAR) in different biological samples. Determination of cellular metabolic phenotype and mitochondrial activity is crucial for precise characterization of the research models and the pathophysiological alterations studied in various research disciplines across the University of Antwerp; including reproductive biology and toxicology, cell biology, neurodegenerative disease, cardiovascular function, cancer, obesity, diabetes, metabolic disorders, immunology, virology and toxicology, amongst others. This is also a key for drug screening and development of new treatment strategies. Seahorse XF analyzers offer the most sensitive and accurate technology with the highest throughput compared to other alternatives. It has contributed to ground-breaking discoveries demonstrated in an increasing number of publications in different research fields about the critical role of metabolism in a wide variety of diseases. It has been successfully applied on various types of cells and tissues including mammalian gametes, primary cells, adherent and suspension cell lines, cells differentiated from induced pluripotent stem cells, isolated mitochondria, 3D cultures, Zebrafish and mammalian embryos, roundworms, fruit flies and yeast. Adding to the broad applicability of the platform, the XF technology employs a label-free, non-invasive methodology allowing samples to be used post-measurement for other investigations. The Seahorse XFp Analyzer will directly contribute to several ongoing and future research within laboratories belonging to different departments and faculties at UA. Furthermore, this new platform will not only facilitate our on-site accessibility, but will also increase our national and international competitiveness. It will further support multidisciplinary networking and collaboration and shall further increase our scientific research excellence.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: De Meyer Guido
• Co-promoter: Knapen Dries
• Co-promoter: Timmerman Vincent

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

In humans, female infertility is an ongoing problem with an estimated prevalence of around 10%. Worldwide, obesity and overweight reached epidemic proportions and there is strong evidence for their link with infertility. The metabolic profile of obese women is commonly characterized by altered levels of blood parameter values. The latter is well reflected in the reproductive fluids and is believed to negatively affect fertility. Recent studies are shedding light on new forms of embryo–maternal communication via the delivery and/or exchange of extracellular vesicles, newly identified information carriers that exist in the uterine fluid. Animal models are valuable for basic and applied research in the field of reproductive biology especially due to ethical limitations and restricted availability of human biological material. Due to many similarities between bovine and human reproductive physiology, the cow has become a well-established and relevant model for human reproductive research. We hypothesise metabolic stress, as similarly described between obese women and lactating cow, is a key role player negatively affecting the uterine environment during early pregnancy. To proof this theory, we aim to perform novel in vivo and in vitro studies to unravel factors affecting the embryo-maternal cross talk in metabolically stressed dairy cows, focusing on the role of extracellular vesicles

Researcher(s)

• Promoter: Leroy Jo
• Fellow: Bogado Pascottini Osvaldo

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

Obesity is becoming a global threat, reducing mother's health and reproductive capacities and affecting the offspring's health. Clear preconception care guidelines for obese future mothers are lacking. Clinical studies are flawed and fundamental studies in basic animal models are scarce. The importance of preconception weight loss on reproduction and baby's health is heavily debated and has never been investigated in detail. This project aims to uncover the role and the importance of clinically relevant preconception care advices to obese women planning for pregnancy. To do so, we propose strategically designed fundamental obese mouse models to assess the impact of preconception weight loss, diet normalization, increased physical activity, omega-3 rich diet or the combination thereof. We will focus on four distinct major research challenges: 1) can we find improvements of mother's metabolic profile before conception in relation to the observed weight loss; 2) does the mother's own fertility success increase; 3) can we improve the postnatal health of the offspring and 4) can we safeguard the offspring's reproductive physiology. Physiological and in depth molecular outcome parameters will be combined to generate a clear and integrated view on the effects of preconception care lifestyle interventions. If successful, these novel insights will be the basis for developing future awareness and education programs aiming at improved human maternal health at the time of conception.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: Bols Peter
• Co-promoter: De Neubourg Diane
• Co-promoter: Marei Waleed

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

A disturbed maternal metabolism like in obesity or type II diabetes has clearly been associated with disappointing fertility. We extensively showed that such metabolic disorders have direct effects on the micro-environment of the growing and maturing oocyte, ultimately leading to reduced oocyte and embryo quality. Obesity is a global health threatening problem and recent studies indicated that maternal obesity may result in significant health issues in the offspring. More in depth mechanistic research clearly pointed out the importance of uterine programming in early pregnancy. It is not known however whether the metabolic status of obesity as such and/or potential direct effects of the typical fat rich western type diet are responsible for these observations. Based on the epidemiological relevance of obesity and hypercholesterolemia we hypothesize that obesity or an obesogenic diet of the mother around conception or during the entire pregnancy will alter the micro-environment of the growing embryo and fetus. This will change uterine programming ultimately leading to compromised offspring's health and reproductive physiology. To systematically investigate this hypothesis, we will feed female LDLR knock-out mice (LDLR-/-) an obesogenic diet A) several weeks before conception resulting in maternal obesity at conception or B) solely around conception or C) throughout the entire pregnancy. The offspring will be cross-fostered upon birth and will be used to study the general health of the offspring, the ovarian follicular reserve and the process of folliculo- and oogenesis, the offspring's pre-implantation embryo physiology and gene expression pattern and the receptivity of the offspring's uterus to support full pregnancy resulting in healthy offspring. By using this strategic experimental model we will be able to find the most sensitive window during pregnancy for uterine programming of reproduction, and it allows us to study the effects on every specific step on reproductive functioning. We believe that this project proposal may significantly contribute to the concept of "Developmental Origin of Health and Fertility" by further spreading the knowledge that epigenetic effects of maternal metabolism and diet may jeopardize health but also fertility in the offspring.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: De Keulenaer Gilles
• Co-promoter: Marei Waleed
• Fellow: Moorkens Kerlijne

Research team(s)

• Veterinary physiology and biochemistry

Project website

Project type(s)

• Research Project

Abstract

Subfertility represents a major problem in domestic animals and humans. In cattle but also in women, up to 40% of total embryonic losses occur between days 7 and 16 of pregnancy, indicating that early embryonic mortality is a major cause of reproductive failure. A finely tuned synchrony between the competent embryo and a receptive endometrium is the key for optimal embryo development and the establishment of a successful pregnancy. Several studies have indicated the existence of complex paracrine and endocrine in vivo communication between early embryo and the maternal tract in mammals. However, so far there is no evidence that the embryo significantly interacts with the endometrium before elongation in the cow (begins 13 days post-mating) or before real implantation in human (day 10-17), while most of the early embryonic losses happen at that time. To understand the pathways of early pregnancy loss we have to elucidate the physiological molecular and biochemical processes underpinning and regulating the earliest maternal-embryonic cross talk upon the moment of embryo arrival in the uterus. In the present project, using the cow as a proven research model to study the very first developmental stages of the pre-implantation embryo, our central aim is to study the embryo/conceptus and endocrine programming of the endometrium to support pregnancy success. In the first part of the PhD research (Milestones 1 and 2, conducted at the University of São Paulo) we hypothesized that exposure to an embryo changes the abundance of specific transcripts and the biochemical composition of the uterine fluid in the cranial region of the pregnant uterine horn. As such an effect is likely to be very local in nature, we developed an in vivo model that allowed sampling the endometrium closer to the embryo (Sponchiado et al., 2017). To limit the use of experimental animals, in the second part of the PhD research (Milestone 3), we propose to use an innovative in vitro co-culture system to investigate the nature of the specific interaction between bovine embryos and endometrial epithelial cells and how this ultimately may affect early embryo quality. This part of the project will be conducted at the University of Antwerp. The proposed combination of in vivo and in vitro systems with state-of-the art analytical tools of transcriptome and metabolomic research should reveal a plethora of candidate genes and bioactive molecules to understand the pathways of the very first embryo-maternal dialogue. The very first communication between the mother and her embryo is undoubtedly one of the most exciting processes in reproductive biology. The knowledge of these mechanisms should help to understand the problem of early embryo mortality and pregnancy loss leading to disappointing fertility results. Only then it will be possible to build on preventive and even therapeutic measures impacting in pregnancy success both in human and agricultural application.

Researcher(s)

• Promoter: Leroy Jo

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

Obesity is becoming a global threat, reducing mother's health and reproductive capacities and affecting the offspring's health. Clear preconception care guidelines for obese future mothers are completely lacking. Clinical studies are flawed and more fundamental studies in basic animal models are very scarce. The importance of preconception weight loss on reproduction and baby's health is heavily debated and never been investigated in detail. This research project aims to propose strategically designed animal research models to provide relevant scientific evidence for effective and sustainable preconception care advices to obese women planning for pregnancy. To do so, we will assess the impact of preconception weight loss, diet normalization, increased physical activity, omega-3 rich diet or the combination thereof in obese outbred mother mice on four distinct major outcome parameters: 1) improvement of mother's metabolic profile before conception in relation to the observed weight loss; 2) mother's own fertility success; 3) postnatal health of the offspring and 4) offspring's reproductive physiology. Effective guidelines for preconception care lifestyle interventions in obese patients will drastically lower the (public) health care cost associated with assisted reproduction and should maximally safeguard the health of the baby. The data generated will be the basis for awareness and education programs aiming at improved maternal health at the time of conception.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: De Neubourg Diane
• Fellow: Smits Anouk

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

This project focuses on how strategically applied anti-oxidants in the ratio can improve dairy cow fertility through an improved oocyte and embryo quality. The research will focus on very specific parameters of the oocyte's and embryo's micro-environment and of the quality of the female gamete.

Researcher(s)

• Promoter: Leroy Jo

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

Infertility is a major socio-economic problem affecting millions worldwide and is specifically linked to maternal obesity and other (diet induced) metabolic disorders. Understanding the mechanisms by which altered metabolism affect fertility is crucial for successful interventions. Mitochondria are the power house within the oocyte. Reduced somatic cell mitochondrial function occurs early in the pathogenesis of metabolic diseases. This is mainly due to the lipotoxic effects of elevated free fatty acid concentrations in blood. For the oocyte to be developmentally competent, the number and function of mitochondria should reach a certain threshold. There are several thousands of mitochondria in the mature oocyte derived from about 20 mitochondria in the germ cell. In addition to their bio-energetic roles, mitochondria are also sensors of stress. Oxidative stress and associated cellular damage elicit stress signalling between the mitochondria and the nucleus to start a protective machinery. The effects of metabolic stress on mitochondrial replication and stress responses during oocyte growth and subsequent embryo development are not known. In this project we will use in vitro and in vivo animal models to study mitochondrial functions and stress responses under maternal metabolic stress conditions in growing oocytes. Defect-based protective and rescue interventions will also be tested to investigate opportunities for curative interventions.

Researcher(s)

• Promoter: Leroy Jo
• Fellow: Marei Waleed

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

A disturbed maternal metabolism like in obesity or type II diabetes has clearly been associated with disappointing fertility. We extensively showed that such metabolic disorders have direct effects on the micro-environment of the growing and maturing oocyte, ultimately leading to reduced oocyte and embryo quality. Obesity is a global health threatening problem and recent studies indicated that maternal obesity may result in significant health issues in the offspring. More in depth mechanistic research clearly pointed out the importance of uterine programming in early pregnancy. It is not known however whether the metabolic status of obesity as such and/or potential direct effects of the typical fat rich western type diet are responsible for these observations. Based on the epidemiological relevance of obesity and hypercholesterolemia we hypothesize that obesity or an obesogenic diet of the mother around conception or during the entire pregnancy will alter the micro-environment of the growing embryo and fetus. This will change uterine programming ultimately leading to compromised offspring's health and reproductive physiology. To systematically investigate this hypothesis, we will feed female LDLR knock-out mice (LDLR-/-) an obesogenic diet A) several weeks before conception resulting in maternal obesity at conception or B) solely around conception or C) throughout the entire pregnancy. The offspring will be cross-fostered upon birth and will be used to study the general health of the offspring, the ovarian follicular reserve and the process of folliculo- and oogenesis, the offspring's pre-implantation embryo physiology and gene expression pattern and the receptivity of the offspring's uterus to support full pregnancy resulting in healthy offspring. By using this strategic experimental model we will be able to find the most sensitive window during pregnancy for uterine programming of reproduction, and it allows us to study the effects on every specific step on reproductive functioning. We believe that this project proposal may significantly contribute to the concept of "Developmental Origin of Health and Fertility" by further spreading the knowledge that epigenetic effects of maternal metabolism and diet may jeopardize health but also fertility in the offspring.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: De Keulenaer Gilles
• Co-promoter: Van Hoeck Veerle
• Fellow: Smits Anouk

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

To further expand on this intriguing patho-phsyiological role of elevated NEFA in the problem of subfertility, it need to be addressed whether NEFA can induce epigenetic changes and whether this affects further embryo development and postnatal health. Therefore, this research proposal concentrates on the effect of oocyte maturation under elevated NEFA conditions on DNA methylation patterns in Day 7 embryos, on further pre-implantation in vivo development and on postnatal health and growth. A state of the art in vitro embryo culture and embryo transfer protocols will be used combined with advanced molecular techniques. The integration of data on Day 7 embryo physiology, DNA methylation, further development and postnatal health could provide key metabolic information on the role of elevated NEFA concentrations in reproductive failure.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: Bols Peter
• Fellow: Desmet Karolien

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

Metabolic disorders have a profound effect on many aspects of reproduction. High rates of early embryonic loss are a major issue. Upon arrival in the uterus, the proportion of surviving embryos drops off rapidly, which points towards troubled first interactions between embryonic and endometrial tissues. Recent insights suggest that embryo energy metabolism can be involved, as nutrient-sensing pathways regulate differentiation, the latter being crucial to guarantee the first interplay between embryonic and endometrial cells. During the critical first week of development, the embryo has a remarkable metabolic plasticity that allows to grow and develop, even under suboptimal nutrient environments. At the blastocyst stage, this early metabolic adaptation may come at a cost, ultimately leading to pregnancy failure. Herein, we hypothesise that suboptimal metabolic conditions in the early environment of the embryo can impact on the differentiation signature of the resultant trophoblast cells. This might be 'sensed' by the endometrium. We also propose that a differentiated endometrium has the potency to reset and rebalance the embryonic metabolism. Embryo and endometrial 'go' or 'no-go' responses will be studied using bovine in vitro and in vivo set-ups. While embryo implantation varies among species, the initial events between trophoblast and endometrial cells are shared among mammals, which implies that crossspecies lessons can be learned from the cow.

Researcher(s)

• Promoter: Leroy Jo
• Fellow: Van Hoeck Veerle

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

A disturbed maternal metabolism like in obesity or type II diabetes has clearly been associated with disappointing fertility. We extensively showed that such metabolic disorders have direct effects on the micro-environment of the growing and maturing oocyte, ultimately leading to reduced oocyte and embryo quality. Obesity is a global health threatening problem and recent studies indicated that maternal obesity may result in significant health issues in the offspring. More in depth mechanistic research clearly pointed out the importance of uterine programming in early pregnancy. It is not known however whether the metabolic status of obesity as such and/or potential direct effects of the typical fat rich western type diet are responsible for these observations. Based on the epidemiological relevance of obesity and hypercholesterolemia we hypothesize that obesity or an obesogenic diet of the mother around conception or during the entire pregnancy will alter the micro-environment of the growing embryo and fetus. This will change uterine programming ultimately leading to compromised offspring's health and reproductive physiology. To systematically investigate this hypothesis, we will feed female LDLR knock-out mice (LDLR-/-) an obesogenic diet A) several weeks before conception resulting in maternal obesity at conception or B) solely around conception or C) throughout the entire pregnancy. The offspring will be cross-fostered upon birth and will be used to study the general health of the offspring, the ovarian follicular reserve and the process of folliculo- and oogenesis, the offspring's pre-implantation embryo physiology and gene expression pattern and the receptivity of the offspring's uterus to support full pregnancy resulting in healthy offspring. By using this strategic experimental model we will be able to find the most sensitive window during pregnancy for uterine programming of reproduction, and it allows us to study the effects on every specific step on reproductive functioning. We believe that this project proposal may significantly contribute to the concept of "Developmental Origin of Health and Fertility" by further spreading the knowledge that epigenetic effects of maternal metabolism and diet may jeopardize health but also fertility in the offspring.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: Schrijvers Dorien
• Fellow: Karamtzioti Paraskevi

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand the Hercules Foundation. UA provides the Hercules Foundation research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Maes Louis
• Co-promoter: Delputte Peter
• Co-promoter: De Meyer Guido
• Co-promoter: Dewilde Sylvia
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Lambeir Anne-Marie
• Co-promoter: Lebeer Sarah
• Co-promoter: Leroy Jo
• Co-promoter: Van Cruchten Steven
• Co-promoter: Wenseleers Wim

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

This research project concentrates on the effect of oocyte maturation, fertilization and embryo culture under high NEFA conditions on fertilization rate, DNA transcription and methylation patterns in Day 7 embryos.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: Bols Peter
• Co-promoter: Van Cruchten Steven

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand the Flemish Public Service. UA provides the Flemish Public Service research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Leroy Jo

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

To further expand on this intriguing patho-phsyiological role of elevated NEFA in the problem of subfertility, it need to be addressed whether NEFA can induce epigenetic changes and whether this affects further embryo development and postnatal health. Therefore, this research proposal concentrates on the effect of oocyte maturation under elevated NEFA conditions on DNA methylation patterns in Day 7 embryos, on further pre-implantation in vivo development and on postnatal health and growth. A state of the art in vitro embryo culture and embryo transfer protocols will be used combined with advanced molecular techniques. The integration of data on Day 7 embryo physiology, DNA methylation, further development and postnatal health could provide key metabolic information on the role of elevated NEFA concentrations in reproductive failure.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: Bols Peter
• Fellow: Desmet Karolien

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand the Province of Antwerp. UA provides the Province of Antwerp research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Leroy Jo

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: Hermans Nina
• Fellow: De Bie Jessie

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

Previous research work revealed that metabolic changes, associated with the growing incidence of obese individuals and diabetics, might have harmful repercussions for the reproductive outcome. The consequences of hyperglycemia, due to obesity and diabetes, have already been investigated thoroughly in rats and mice. This research project rather involves another feature of these metabolic pathologies: the high free fatty acid concentrations in blood. The interest of the human assisted reproduction society in a bovine model to assess the influence of free fatty acids on the oocytes developmental competence, on the viability and function of the granulosa cells and the inquisitiveness to the underlying mechanism of these potential effects, imposes us to further research.

Researcher(s)

• Promoter: Bols Peter
• Co-promoter: Leroy Jo
• Fellow: Van Hoeck Veerle

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

This project represents a formal service agreement between UA and on the other hand VIB. UA provides VIB research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Leroy Jo

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

The project focuses on the long term culture of pre-antral follicles opens a whole new approach and frame work making it possible to study the effects of maternal nutrition and metabolism on the pre-ovulatory follicles and growing and maturing oocytes.

Researcher(s)

• Promoter: Leroy Jo
• Fellow: Arias Alvarez Maria

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

A disturbed maternal metabolism may induce disappointing fertility and may jeopardize the offspring's health. Only recently, the importance of the early developmental stages in life has gained scientific attention in subfertility research. This project focuses on the metabolic and (epi)genetic consequences of long-term elevated non-esterified fatty acid (NEFA) serum concentrations in the dam on ovarian physiology, oocyte and embryo quality. Elevated NEFA cocnetrations are a key factor in several metabolic disorders such as diabetes, negative energy balance and obesitas and is typical for lipolysis. Previous research showed already that these elevated NEFA concentrations are reflected in the follicular fluid of the dominant follicle and that they cause a reduction in the oocyte's developmental competence. To mimic the in vivo situation even better and to substantiate the causative role of elevated NEFA in the pathogenesis of subfertility, a long term exposure model during the process of follicular growth should be developed. Therefore murine secondary follicles will be isolated and will be cultured for 12 days. These growing and maturing follicles will be exposed to elevated NEFA conditions and the effects on folliculogenesis, oocyte developmental competence and embryo quality will be studied in detail.

Researcher(s)

• Promoter: Leroy Jo

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

A disturbed maternal metabolism may induce disappointing fertility and may jeopardize the offspring's health. Only recently, the importance of the early developmental stages in life has gained scientific attention in the study of the pathogenesis of subfertility. This project focuses on the metabolic and (epi)genetic consequences of long-term elevated non-esterified fatty acid serum concentrations in the dam on folliculogenesis, oocyte developmental competence and embryo quality.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: Bols Peter
• Co-promoter: Knapen Dries

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand the Federal Public Service. UA provides the Federal Public Service research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Bols Peter
• Co-promoter: De Coen Wim
• Co-promoter: Knapen Dries
• Co-promoter: Leroy Jo

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

This is a fundamental research project financed by the Research Foundation - Flanders (FWO). The project was subsidized after selection by the FWO-expert panel.

Researcher(s)

• Promoter: Bols Peter
• Co-promoter: Leroy Jo

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

Making the fatty acid composition of the human diet more poly-unsaturated is generally proposed as beneficial for health. This combined in vivo and in vitro bovine research model will elucidate the direct consequences of such a fatty acid shift on follicular fluid composition, on oocyte and embryo quality. Earlier work on dairy cows revealed several contradicting results, indicating the need for more in depth research.

Researcher(s)

• Promoter: Leroy Jo

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand the Province of Antwerp. UA provides the Province of Antwerp research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: Bols Peter

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

Previous research work revealed that metabolic changes, associated with the growing incidence of obese individuals and diabetics, might have harmful repercussions for the reproductive outcome. The consequences of hyperglycemia, due to obesity and diabetes, have already been investigated thoroughly in rats and mice. This research project rather involves another feature of these metabolic pathologies: the high free fatty acid concentrations in blood. The interest of the human assisted reproduction society in a bovine model to assess the influence of free fatty acids on the oocytes developmental competence, on the viability and function of the granulosa cells and the inquisitiveness to the underlying mechanism of these potential effects, imposes us to further research.

Researcher(s)

• Promoter: Bols Peter
• Co-promoter: Leroy Jo
• Fellow: Van Hoeck Veerle

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

Hypercholesterolemia is a human disorder and it has been associated with an unhealthy eat pattern. This combined in vivo and in vitro bovine model will elucidate the effect of nutritionally induced hypercholesterolemia on oocyte and embryo quality. In earlier work we showed that the metabolic changes in dairy cows early post partum and their consequences on oocyte and follicle quality is a valuable model for research in human infertility.

Researcher(s)

• Promoter: Leroy Jo

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project