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Safeguarding medically assisted reproduction
Mulder, C.L.
Publication date2018Document VersionOther
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Citation for published version (APA):Mulder, C. L. (2018).
Safeguarding medically assisted reproduction.
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CHA
PTeR 1
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General introduction and outline of this thesis
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Chapter 1
12
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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Safeguarding medically assisted reproduction
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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Chapter 1
14
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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15
Safeguarding medically assisted reproduction
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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Chapter 1
16
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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Safeguarding medically assisted reproduction
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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Chapter 1
18
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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Safeguarding medically assisted reproduction
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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