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Safeguarding medically assisted reproduction

Mulder, C.L.

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Citation for published version (APA):Mulder, C. L. (2018). Safeguarding medically assisted reproduction.

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PTeR 1

General introduction and outline of this thesis

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General introduction

The precise biological conditions in which we have been conceived are for most of us unknown. The development of Assisted Reproductive Technology (ART) has enabled us to influence the conditions in which two gametes join to create a new individual. And with the development of novel reproductive technology we might be able to actu-ally create gametes from somatic cells in the future. Currently we only have minimal information if these manipulations of our gametes and embryos may affect our health and the health of our offspring. According to the Developmental Origins of Health and Disease (DOHaD) concept, early life conditions will influence your health later in life. But from which developmental stage is an organism vulnerable to external exposures? Is it once an oocyte is fertilized by a single spermatozoon? Or can environmental influences during the formation of our gametes already influence the health of the child-to-be? Could these effects be transmitted transgenerationally, and therefore not only affect the child, but also his or her children’s children?

Transgenerational inheritance of acquired traits has been a source of debate for the past centuries. The popular assumption “like begets like” has resonated through history. Before the identification of DNA as the carrier of hereditary information, the health status, life-style and sometimes even occupation of the father was thought to have an effect on the health of the offspring (Crothers, 1887; Armstrong, 2003). On a scientific basis, Lamarck was one of the first to provide rationale supporting this concept. In his theory on evolution he used the long neck of the giraffe as an example for the inheri-tance of acquired traits: the giraffe had acquired a longer neck since its ancestors had been reaching high branches for food for many generations (Lamarck, 1809). Hence, he suggested that the cumulative experience of ancestors has a formative effect on the offspring. In the same era August Weismann published his theory on heredity, where he specified that only the germ plasm contains information that was heritable across generations (Weismann, 1889). This implies that environmentally induced effects on the soma cannot be transmitted to subsequent generations. However, a popular belief of Weismann contemporaries was that exposure to germ poisons, such as the consumption of alcoholic substances, would be imprinted in the germ plasm and have detrimental effects on offspring (Forel, 1893). Hence noxious substances could even affect a child before it was even conceived.

Despite the fact that conception is often seen as the start of life, life in fact can be considered a continuous process that has neither a beginning nor an end, also known as the circle of life. Our gametes, i.e. spermatozoa and oocytes, are then considered living entities which are capable to transfer information across generations. If one combines the concept of continuity of life with the theory of Lamarckian evolution and germ

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1poison, one ends up with an idea resembling a perpetuum mobile: a never-ending cycle of exposure and effect across generations.With the rise of Medically Assisted Reproduction (MAR) in recent decades, it has

become increasingly important that we gain knowledge on the effect that manipulation of our gametes and embryos may have on the health of the offspring. MAR is used as an umbrella term to define all reproduction brought about by various medical interven-tions. It includes all ART, which is currently defined “all interventions that include the in vitro handling of both human oocytes and sperm or of embryos for the purpose of reproduc-tion” (Zegers-Hochschild et al., 2017). These treatments have been and are still evolving into more complex procedures, which harbour unknown effects on those that undergo these treatments (i.e. the parents-to-be) and on his or hers offspring and the genera-tions thereafter. In this thesis the health consequences of selected novel and existing MAR techniques will be discussed.

Background

Subfertility and Medically Assisted Reproduction

Subfertility affects approximately 15% of all couples, and is defined as “the failure to establish a clinical pregnancy after 12 months of regular, unprotected sexual intercourse or due to an impairment of a person’s capacity to reproduce either as an individual or with his/her partner” (Zegers-Hochschild et al., 2017). The underlying cause of this subfertility var-ies and can be associated with a male factor (e.g. insufficient sperm quality or quantity), female factor (e.g. blocked fallopian tubes, or advanced age), both, or unknown cause (Johnson, 2007). In some cases a genetic, endocrine or developmental cause can be identified (Matzuk and Lamb, 2008).

Given the wide range of nature and the severity of subfertility, a variety of MAR tech-niques can help these couples conceive. in vitro fertilization (IVF) is since its introduction in 1978 a commonly used technique (Steptoe and Edwards, 1978). This technique was originally developed to by-pass blocked fallopian tubes. During this procedure, the ovaries are hyperstimulated using gonadotropins to produce an increased number of mature follicles, and after retrieval the oocytes are incubated with ejaculated and pro-cessed spermatozoa of the man. Intracytoplasmic Sperm Injection (ICSI) allows patients with oligozoospermia (i.e. an insufficient amount of spermatozoa) or asthenozoosper-mia (i.e. low motility) to father a child as it directly injects the sperm into the cytoplasm of the oocyte (Palermo et al., 1992). If the ejaculate is devoid of mature spermatozoa, spermatozoa can surgically be retrieved from the epididymis through percutaneous or microsurgical epididymal sperm aspiration (PESA/MESA) (Patrizio et al., 1988, Silber et al., 1990) or from the testicle through testicular sperm extraction (TESE). The spermatozoa

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retrieved during these procedures, can then be utilized for ICSI (Devroey et al., 1995). For these therapies both the mother and the father need to provide a mature gamete.

For some couples it is impossible to provide both mature spermatozoa and oocytes that can be utilized for IVF-related therapies. For example if no spermatozoa are found upon TESE or if no mature oocytes can be retrieved, IVF or ICSI is not possible. Genetic parenthood seems therefore not feasible for these couples. The same holds true for single parents or same-sex couples. The use of donor gametes then remains the sole option for these patients to partly achieve genetic parenthood.

In an increasing proportion of patients, infertility is the result of previous exposure to gonadotoxic treatment, e.g. as part of a cancer therapy. Fertility preservation is therefore of importance for those at risk of becoming infertile. Fertility preservation is defined as “various interventions, procedures and technologies, including cryopreservation of gam-etes, embryos or ovarian and testicular tissue to preserve reproductive capacity” (Zegers-Hochschild et al., 2017). For those that are able to provide a mature gamete, the gametes derived from them can be cryopreserved for later use. For adult male cancer patients a semen sample can be cryopreserved prior to gonadotoxic treatment. For female cancer patients in their reproductive age either embryos conceived via IVF, oocytes or ovar-ian tissue can be cryopreserved. For prepubertal girls ovarian tissue cryopreservation can be offered. In the case of ovarian tissue cryopreservation, ovarian tissue grafting provides a way for these patients to conceive (Greve et al., 2012; Rodriguez-Wallberg and Oktay, 2012).

Some patients cannot provide mature gametes for cryopreservation, including prepu-bertal boys. For prepubertal male cancer patients a testicular biopsy can be taken prior to the gonadotoxic treatment (Ginsberg et al., 2010). Despite the fact that spermatogen-esis has not commenced yet in these boys, the spermatogonial stem cells (SSCs), that have the potential to initiate spermatogenesis, are already present. At initiation of this PhD project, different techniques that could help these boys were in development, that can be broadly divided in (1) transplantation of (cultured) spermatogonial stem cells to the patient resulting in in vivo differentiation of the cells and restoration of fertility, designated spermatogonial stem cell autotransplantation (SSCT) (Schlatt, 2002; Brinster, 2007) and (2) by differentiation using organ culture to produce these cells in vitro or in vivo by subcutaneous or scrotal grafting (Orwig and Schlatt, 2005; Wyns et al., 2007; Jah-nukainen and Stukenborg, 2012) and (3) in vitro production of sperm cells from induced pluripotent stem cells (Eguizabal et al., 2011; Yang et al., 2012)

Safety of currently used Medically Assisted Reproductive Techniques

In the years preceding the birth of Louise Brown, the first child born from IVF, the idea of creating new life in the lab was raising fear not only in the general public, but among scientists as well. People feared that children conceived outside of the womb would be

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1born as monstrosities, children with severe congenital anomalies. But when Dr. Patrick Steptoe and Dr. Robert Edwards reported the birth of “a normal healthy infant girl weigh-ing 2700 g” after reimplantation of human embryo in 1978 (Steptoe and Edwards, 1978), feelings of reassurance started to spread throughout society. Acceptance of IVF as a treatment of subfertile patients increased at a revolutionary pace and worries about the (long-term) health of this children subsided rapidly (Marantz Henig, 2004).

As the cohort of MAR-conceived children grows, an increasing amount of data on the health risks of MAR has become available. Despite the happiness that IVF has brought to those that could have not conceived otherwise, it has become clear that this treatment is not fully without risks for both the mother and the child. Women that are undergo-ing IVF-treatment, are at risk of developing ovarian hyperstimulation syndrome, which develops in 0.05–3% of all hyperstimulated women (Mathur et al., 2000; Gelbaya, 2010; Luke et al., 2010). Moreover, there is an increased risk of obstetric and perinatal com-plications, including pregnancy hypertension, the risk of preterm birth, being small for gestational age and perinatal mortality for women conceiving through IVF (Pandey et al., 2012). Furthermore, children born after IVF/ICSI treatment are 150 grams lighter at birth compared to those that are naturally conceived (-149.33 grams birthweight, 95% CI -161.91 - -136.74 grams) as shown in a meta-analysis reported in 2012 on 14.623 IVF /ICSI children and 19.004 natural conception controls (Pandey et al., 2012). Another systematic review published in 2012, showed an increased risk of congenital anomalies in children conceived through IVF/ICSI (n=124.468) compared to naturally conceived children (Risk Ratio of 1.37, 95% CI 1.26–1.48) (Wen et al., 2012). A similar increased risk for congenital anomalies was found in a large birth cohort, with a multivariate-adjusted odds ratio of 1.28 (CI-1.16-1.41) when comparing the frequency of birth defects in 6163 IVF/ICSI derived neonates in a cohort of 308.973 live births (Davies et al., 2012). There are also signs that IVF and ICSI are associated with an increased risk of imprinting disorders such as Beckwith-Wiedemann Syndrome (BWS) in the offspring (DeBaun et al., 2003; Källén et al., 2005; Lidegaard et al., 2005), although this finding is still heavily debated since this association is largely based on case studies or small case series (Odom and Segars, 2010).

In 2012, a surge of papers were already released on the long-term health IVF-ICSI children. Reassuringly, some papers found no health effect of IVF on neurological and cognitive functioning (Montgomery et al., 1999; Middelburg et al., 2009; Källén et al., 2011; Lehti et al., 2013), the development of vision and hearing (Ludwig et al., 2010) or cancer incidence (Dommering et al., 2012; Foix-Lhlias et al., 2012). Others reported a higher risk for cerebral palsy (Strömberg et al., 2002; Zhu et al., 2010), Langerhans cell histiocytosis (Åkefeldt et al., 2012), abnormal vascularization of the eye (Wikstrand et al., 2008), colour blindness, retinoblastoma and childhood leukaemia (Moll et al., 2003; Petridou et al., 2012) in children conceived through IVF/ICSI compared to naturally con-ceived or the general population.

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It thus appears that IVF/ICSI has a significant impact on the child’s health at different stages of development. One can argue that the differences that are found are the mere result of the subfertility of the parents, and not per se from IVF/ICSI related techniques. Since culture is an indispensable step of most MAR techniques, people have argued that the embryos or gametes might adapt to this artificial environment and that this affects development (Fernández-Gonzalez et al., 2007; Morgan et al., 2008; Eppig et al., 2009; Calle et al., 2012a, 2012b). The hypothesis is then that the health effects that are seen in these children arise as a result from this time spend in vitro.

Developmental programming and epigenetics

The fact that our environment influences us from an early stage has gained attention in the last century. The DOHaD hypothesis was coined by the British epidemiologist David Barker, when he described the relationship between intra-uterine growth restriction, low birth weight and premature birth, and an increased risk for vascular diseases and diabetes later in life (Barker, 1990, 2004). He hypothesized that a suboptimal intra-uterine nutritional status would force the embryo or foetus to adapt to this suboptimal environment, leading to adverse effects later on in development and in adulthood.

The Dutch Famine cohort and the Överkalix cohort are famous examples where such a transgenerational effect of food-availability was indeed recognized. In the Dutch Hunger Winter studies, maternal famine could be linked to an altered disease susceptibility of her children later in life, including an increased risk of cardiovascular diseases, diabetes and breast cancer (De Rooij et al., 2006; Painter et al., 2006, 2008; Roseboom et al., 2011). In the Överkalix cohort, restricted food supply of the grandfather was connected to the mortality rate of his grandchildren which occurred in a sex-specific manner as well (Pembrey et al., 2006). In other words, acquired traits early in our development influence us for the rest of our lives. It is thus of evident importance to gain a better understanding of the mechanisms that underlie the adaptation of the early human embryo.

The mechanisms through which the embryo may adapt to its environment are thought to be epigenetic in nature. The term epigenetics, literally upon- or above- genet-ics, was coined as early as in the 1940s by developmental biologist Conrad Waddington. He described epigenetics as the interactions of genes with their environment which bring the phenotype into being (Waddington, 1942a, 1942b). Currently an epigenetic trait is defined as “…a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence” (Berger et al., 2009). Even though the recent definition reflects more on the actual molecular biology behind this term, Waddington’s original hypothesis hints towards the possibility of acquired traits.

Epigenetic tags, including DNA methylation, histone modifications and miRNAs, are often viewed as memory of the cell. This cellular memory is important for cell fate and is replicated during cell division. In the light of exposure during critical stages of

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1development, epigenetic alterations might be a mechanism through which the cell remembers its previous state and therefore be able to adjust to the exposure more efficiently. This may lead to a difference in disease risk and health later in life (Jiménez-Chillarón et al., 2012). Indeed, when one compares the DNA methylation status of specific genes in blood of adult individuals exposed to famine peri-conceptionally to unexposed siblings, specific epimutations can be found (Heijmans et al., 2008; Tobi et al., 2009).

Indispensable aspects of MAR, including the culture of embryos or germ cells, can be seen as the summit of peri-conceptional exposure. IVF/ICSI embryos are cultured for 3-5 days prior to transfer to the mother’s womb. Prior to initiation of this project, a few papers described differences in the DNA methylation status throughout the genome (Katari et al., 2009), but mostly in parental imprinted genes (Kobayashi et al., 2007; Gomes et al., 2009; Katari et al., 2009; Shi et al., 2011) in children conceived through IVF/ICSI. In a systematic review on this subject published in 2011, six out of seven studies reported changes in DNA methylation and expression of selected genes, amongst oth-ers, in human placenta and cord-blood in children born from IVF/ICSI (Batcheller et al., 2011).

The exact aetiology of these epimutations and the effect that it might have on the health of the offspring was still unknown. Interestingly, the choice of IVF culture medium was shown to have an effect on birthweight (Dumoulin et al., 2010; Nelissen et al., 2012; Vergouw et al., 2012). This was confirmed in animal studies, where the use of different embryo culture media was associated with a difference in the methylation and expression of imprinted genes (Mann, 2004; Market-Velker et al., 2010). Therefore it has been suggested that IVF culture medium may play a crucial role in the mechanisms that underlie the alterations found in health in MAR-derived offspring.

Also in the novel technique SSCT, culture is a crucial step. In SSCT, the number of SSCs obtained from the prepubertal testicular biopsy needs to be expanded before success-ful autotransplantation to the adult testis is feasible. It has been estimated that approxi-mately 50 days of in vitro propagation is necessary to achieve an adequate number of SSCs that would allow for efficient repopulation of the adult testis (Sadri-Ardekani et al., 2009, 2011). Within this culture period, the SSCs are subjected to a different environment than in vivo. At the start of this project only limited information was available about the hazards that transplantation of these cultured SSCs could pose to the recipient of the transplantation or his offspring (Goossens et al., 2009). Studies in mouse showed that SSCs in culture remained (epi)genetically stable over a culture period of two years (Kanatsu-Shinohara et al., 2005), even though DNA methylation levels of only few genes were studied.

Most of the studies performed on SSCT in mouse focussed on the functionality of the culture or transplantation technique, and provided some information on the health status of the pups (Kanatsu-Shinohara et al., 2003; Ryu et al., 2007; Goossens et al., 2009,

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2010; Kubota et al., 2009; Lee et al., 2009; Yuan et al., 2009; Wu et al., 2012), although careful examination on general health and neurodevelopment of these mice was still lacking. Also, the long-term health effects of recipients transplanted with in vitro propa-gated SSCs has largely been neglected.

In 2009, three years before the initiation of this PhD project, the Academic Medical Center obtained CCMO approval from the Dutch Government to collect and cryopre-serve testicular biopsies from prepubertal boys with cancer. This milestone was a impor-tant step towards actual clinical implementation of SSCT in the future. Therefore, the safety of this novel form of MAR for both recipient and offspring needed to be studied in a systematic fashion.

Outline of this thesis

It is needless to say that reproductive techniques should be as safe as possible for the patients and their offspring and that this should be tested prior to clinical introduction of the technique. Therefore, in this thesis we aimed to study the safety of medically assisted reproduction, by scrutinizing the effects of the novel and unimplemented Spermatogonial Stem Cell Transplantation technique as well as the commonly used IVF technique. We aimed to elucidate important aspects of this matter by investigating the direct health effects of MAR in animal models, as well as their effect in human tissues.

The general questions addressed in this thesis are:1. Which hurdles need to be overcome prior to clinical implementation of SSCT?2. Is testicular transplantation of in vitro propagated spermatogonial stem cells associ-

ated with increased cancer incidence after a long-term follow-up?3. Could patient groups other than childhood cancer survivors benefit from spermato-

gonial stem cell transplantation?4. Does culturing inherent to MAR, including IVF and subsequent embryo culture,

induce epigenetic changes in the placenta of IVF conceptae?5. Which general steps need to be overcome to assess safety prior to clinical applica-

tion of novel MAR?Chapter 2 describes the current knowledge on critical assets of Spermatogonial Stem Cell Transplantation (SSCT) as a promising reproductive technique to restore fertility in male childhood cancer survivors. These assets include propagation of SSCs in vitro, genetic and epigenetic stability of SSCs while in culture, and risks that this therapy may pose on the recipient of this transplantation and his offspring. In this chapter several hurdles are identified that are crucial to overcome prior to clinical application of SSCT.

In chapter 3 the data of a pre-clinical animal study on the effect of SSCT on the gen-eral health of the recipient is presented. This study, which was designed to resemble a

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1prospective cohort study, included a life-long follow-up of mice transplanted with in vitro propagated murine spermatogonial stem cells. Cancer incidence and survival time were monitored.

Chapter 4 explores the possibilities of SSCT for patient groups other than childhood cancer survivors. Combining recent genomic editing techniques, including the CRIPSR-Cas9 system with SSCT, may allow the expansion of SSCT to different patient groups. Current knowledge and feasibility of the SSCT in adult patient groups are discussed in this chapter.

In chapter 5 a follow-up study of a previously conducted randomized controlled trial on the effect of IVF culture media on IVF conceptae is presented, in which the level of DNA methylation of imprinted genes in human placenta derived from natural conceptions and IVF conceptions exposed to HTF or G5 embryo culture medium is being measured.

In chapter 6 we present a blueprint for systematic preclinical safety testing of novel reproductive techniques involving an array of tests in a mouse model.

Chapter 7 provides an interdisciplinary discussion of the data presented in this thesis as well as a discussion on the broader (clinical) implications of this work.

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