Epigenetics and donor eggs
Epigenetic changes are reversible alterations to DNA (deoxyribonucleic acid, the genetic code) that do not alter the code itself but can influence how an embryo develops.i The collection of epigenetic changes is often called the epigenome. The dynamic interaction between inherited genetic information and environmental influences shapes the overall epigenetic profile of gametes (oocytes and sperm), the developing embryo, and fetus.ii Epigenetic changes are especially important during critical periods like prenatal development, where the epigenetic landscape is particularly sensitive to external cues.iii
Epigenetic alterations allow for adaptation in response to environmental influences. For example, if a pregnant woman experiences severe stress, this can potentially lead to epigenetic changes that may alter how stress-responses are expressed in the fetus and later in life.iv,v The combined influence of genetics and environment on an individual’s epigenome can have long-term effects on an individual's health.vi These effects may extend into adulthood, potentially impacting certain traits and/or susceptibility to some conditions .vii
The use of donor eggs, instead of one’s own eggs, in IVF can be a sensitive issue and there are often questions about biological impacts of the donor recipient. There are many ways to build families and it is important that donor egg recipients appreciate that their role in their child’s development extends vastly beyond the child’s DNA sequence.
What is epigenetics?
Our DNA contains over 20,000 genes. The specific DNA sequence in our genes is what determines our traits and characteristics. Epigenetics does not alter this genetic code. The term “epigenetics” originates from the Greek word "epi" meaning “over” or “above”, indicating an influence over the genome. Epigenetics is the study of how our behaviors and the environment in which we live can affect the way our genes are interpreted without changing the actual DNA sequence.viii
One can think of epigenetic marks as chemical molecules that act as “tags” or ”labels” on our genes. The “epigenome” is therefore the set of all these tags and acts as instructions to determine when genes are turned on or off.ix Epigenetic tags do not change the gene’s DNA sequence, but rather influence how genes are read or “expressed,” impacting a wide range of the body's functions and development.x During fetal development, epigenetic tags can be added or removed in response to external factors such as nutrition, stress, or exposure to harmful chemicals.xi
There are several types of epigenetic modifications (Figure 2). One of the first clearly identified and most widespread epigenetic modifications is called DNA methylation. This involves attaching a small chemical (methyl molecule) tag to the DNA sequence.xii Certain patterns of DNA methylation can turn off gene expression and are essential for proper human development.xiiiFetal DNA methylation can be influenced by the maternal environment, leading to lifelong health implications for the child. For example, one study demonstrated that elevated maternal blood sugar levels seen in gestational diabetes are associated with demethylation of the fetal gene that codes for the hormone leptin.xivLeptin is a hormone that helps maintain a healthy weight by regulating body fat.xvDemethylation of the fetal leptin gene related to elevated maternal blood glucose may affect the way that child later responds to leptin and can thus impact risk of obesity later in life.xvi
A second common epigenetic alteration is modifications to histone proteins, such as histone acetylation. Acetylation involves adding a different molecular tag, called an acetyl group. xvii Histones are proteins that help organize and package DNA in the cell. To organize and compact DNA, the DNA helix wraps around histone proteins, forming a structure called chromatin. Acetyl tags are added to or removed from specific regions of histones in processes called acetylation and deacetylation. These modifications impact the DNA's compaction, making it easier or harder to read the genetic instructions.xviii Some cell and mouse studies have suggested that maternal alcohol consumption during pregnancy may lead to alterations in histone acetylation in the fetal lung, heart, and other tissues.xix,xx,xxi While more studies are needed to further determine the exact relevance of these epigenetic changes, these early investigations suggest that some of the negative impacts seen in fetal alcohol syndrome may be associated with histone acetylation changes.xxii
Another set of epigenetic alterations are thought to develop from non-coding RNA segments, or RNA sequences that are transcribed but are not translated into proteins.xxiii These non-coding RNAs modify enzymes which change chromatin and alter gene expression.xxiv Epigenetic mechanisms such as DNA methylation, histone acetylation, and non-coding RNA are dynamic.xxv Unlike changes to the DNA sequence, which are typically permanent, many epigenetic modifications are reversible.xxvi Their reversibility is a crucial aspect of epigenetics and suggests the potential for therapies to "reset" epigenetic marks to address specific conditions or diseases. However, the complexity of the process means that reversibility may vary based on the disease and type of epigenetic modification.xxvii
Figure 1. Common types of epigenetic modifications and their impact on gene expression. The human epigenome is complex and the effects are simplified here for easier understanding.
What is gene expression?
In order to understand how epigenetics alters gene expression, it is helpful to understand what “gene expression” is. When a gene is expressed, it means that it is used as an instruction to make ribonucleic acid (RNA), which can then be translated to proteins. The proteins dictate the structure and function of the cells and tissues in the body. In simplified terms, when a gene is transcribed and translated, we say the gene is “expressed." Conversely, some genes can be “turned off” so that they don’t get expressed (they won’t be used to make proteins).
Epigenetic remodeling during fetal development
Soon after fertilization, the initial phases of embryonic development involve a significant episode of epigenetic remodeling, during which most of the epigenetic patterns carried by the parental DNA within the embryo are erased and reprogrammed.xxviii As the embryo goes on to develop from the early two-cell stage to the blastocyst stage, its genetic material changes shape. The folding and organization of the chromatin structure of the embryonic DNA transforms, allowing for more epigenetic changes to occur.xxix
Accurate timing and precision in these processes are crucial to avoid developmental issues or harm to the embryo. If the embryo’s epigenome is not established correctly, this could result in faulty activation of the embryonic genome. This short but crucial phase is vulnerable to influences from the mother’s uterus and the environment in which she lives.xxx
It is worth noting that not all parental epigenetic marks are wiped clean during the remodeling process described above. In the human genetic code, each gene has two versions—one from the sperm cell (paternal) and one from the oocyte (maternal). When the sperm and egg cells mature, some of the genes are marked with unique epigenetic tags, indicating them as either from the sperm or the egg, a process known as genomic imprinting.xxxi Such genes are referred to as “imprinted genes.” Imprinted genes keep their epigenetic programming even during and after the reprogramming period when most of the other epigenetic alterations are wiped clean.xxxii With imprinting, only one of the gene copies inherited is marked to be active (it will be expressed). This creates a "parental signature" on certain genes, meaning that only the maternal or paternal copy will get expressed, not both. If there are changes to these markings, embryo development may be negatively impacted.xxxiii Approximately 99 percent of genes are not imprinted, and in most cases both maternal and paternal copies of the gene get expressed.
Epigenetic effects on developing embryos and fetuses
Some of the first key insights into fetal environmental exposure and future health come from the Dutch Hunger Winter study. This investigation, conducted after World War II, delved into the lasting health effects of exposure to a famine during pregnancy in the Netherlands in 1944-1945.xxxiv It illustrated the potential long-term effects of epigenetic modifications in utero. This study stands out as one of the pioneering investigations into the influence of the maternal environment, and its related epigenetic influence on the health and development of the fetus.xxxv Researchers in this study found that even sixty years later, individuals who were born right after the famine had significantly less DNA methylation of certain genes compared to their unexposed sex-matched siblings.xxxvi This was particularly true for individuals who had been exposed to the famine in the first ten weeks of their fetal development.xxxvii Furthermore, these exposed subjects had an increased risk of health issues such as cardiovascular disease, diabetes, obesity, and psychiatric illness later in life.xxxviii The implication is that epigenetic changes brought on by the maternal environment (e.g., lack of nutrition and stress) can have a lasting impact on future health. The Dutch Hunger study revolutionized our understanding of epigenetics, highlighting how environmental factors during crucial developmental periods can impact long-term health and even affect future generations. xxxix
The Dutch Hunger Winter Study also indicated that there are particularly important times in the early stages of embryo growth when the epigenome is highly responsive to environmental factors. Data from this study suggests the first ten weeks of embryo and fetal development are particularly crucial.xl During this time, it is thought that the embryo is particularly susceptible to epigenetic changes as it is undergoing epigenetic reprogramming, developing organized cell layers, and forming organs.xli, xlii,xliii Factors such as nutrition, exposure to toxins, stress, and specific medications can impact how the epigenome develops during these crucial times (Figure 2). Research highlights the need to know when these critical periods occur in embryonic growth in order to find ways to improve fetal health and avoid potential problems.xliv
Figure 2. The epigenome of the developing fetus and growing child (not shown) can potentially be influenced by positive experiences and habits, such as good nutrition, restful sleep, exercise, supportive relationships, and opportunities for learning. Similarly, negative influences, such as lack of nutrition, toxins, smoking, alcohol, and stress can also impact the epigenome.
Beyond prenatal stages, recipient parents continue to impact epigenetics of their donor-conceived children throughout childhood and adolescence. The child’s environment, including positive experiences such as supported learning and healthy relationships, help shape the child’s epigenome which can influence gene expression into adulthood.
Epigenetics and donor eggs (oocytes) or donor embryos
Epigenetic modifications during fetal development occur whether the oocyte was derived from the intended mother (own eggs), or whether it was a donor egg.
If a donor egg is used to achieve a pregnancy, the genetic code inherited by the resulting child comes entirely from a mix of the egg donor and sperm. In other words, 50 percent of the DNA will come from the donor egg, and 50 percent of the DNA will come from the sperm. Thus, donor-conceived children do not inherit any genes (DNA) from the person giving birth (usually the intended mother).
However, the environment within the uterus of the mother carrying the fetus is obviously very important to fetal development. This comes in the form of providing a healthy intrauterine environment in which the fetus receives nutrients, oxygen, and building blocks to grow, and also includes influencing the epigenome of their offspring. Because of this, while an egg donor-conceived child does not share the same DNA code with their mother, the birthing mother influences their child’s gene expression through epigenetic effects.xlv
Epigenetics involves the interplay between inherited genetic information and environmental factors that can modify gene expression.xlvi The overwhelming majority of epigenetic modifications carried by the parental (egg and sperm) genome are globally reset during the epigenetic reprogramming, which occurs during early embryonic development.xlvii In other words, the epigenetic marks are erased across the genome and new ones will be set. Imprinted genes (about 1 percent of genes) are an exception to this rule as their parental epigenetic signature is not erased.xlviii
Thus, in the context of donor eggs, almost all of the epigenetic information from the egg donor will be removed and then reprogrammed during embryonic and fetal development, Some of the epigenetic reprogramming may be influenced by the environment created within the uterus of the recipient mother .xlix, l While the embryo resulting from the donor egg and sperm may carry some residual epigenetic marks from the egg donor and sperm, a large influence on the developing embryo's epigenetic profile comes from the recipient mother carrying the embryo/fetus.li Following birth, parents continue to provide an environment that will influence epigenetic changes throughout childhood and adolescence.
Overall, it is important to understand that donor-conceived children will not directly inherit genes from the intended mother/the person giving birth to them. However, this individual has an extremely important role in shaping the donor-conceived child both pre- and post-natally, starting from embryonic development. Epigenetics is just one way in which this impact is manifested.
Fertility treatments and epigenetics
Advanced reproductive technology (ART) procedures such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) involve manipulating sperm and oocytes outside of the body to develop a fertilized embryo which is grown for several days before it is placed into the uterus. This means that the embryo is outside the body during at least part of the critical period of epigenetic reprogramming. It is unclear what if any effect this laboratory environment has on the reprogramming process.lii While studies demonstrate that ART is associated with higher rates of fetal and maternal complications such as low birth weight, placental anomalies, and pre-eclampsia, the evidence does not link these outcomes to alterations in the fetal epigenetics.liii
Although it is theoretically possible that ART impacts the fetal epigenome, there is currently a lack of consistent evidence to support this theory. Studying potential impacts is limited due to the diverse nature of ART procedures, discrepancies in tissue samples, heterogeneity of the epigenome, and variations in detection techniques.liv Furthermore, many variables such as maternal age, underlying causes of infertility, and specific ART methods are often not detailed in the studies. A 2024 metanalysis of genome-wide studies that assessed epigenetic alterations during embryonic development did not conclusively identify widespread or consistent effects of ART on global methylation patterns.lv Recall that DNA methylation is a type of epigenetic modification (discussed above).
Controlled ovarian stimulation (COS) during IVF) has been previously linked to changes in DNA methylation patterns during the maturation of oocytes. Research suggested that the heightened hormonal environment during COS could affect the formation of DNA methylation marks, potentially influencing gene regulation in the developing embryo.lvi A meta-analysis conducted in 2022, covering 12 studies examining genome methylation patterns, indicated that offspring resulting from ART may have different methylation patterns compared to those from natural conception.lvii However, the conclusions are subject to debate due to the diversity among the studies.lviii Additionally, a 2019 study on a distinctive group of individuals conceived through ART, with blood collected at birth and in adulthood (between 22 and 35 years old), found that later in adulthood there was no evidence of changes in DNA methylation patterns compared to individuals conceived without ART.lix
Another potential impact on epigenetics is a reported increased risk of imprinting disorders in embryos created using assisted reproductive technology, such as IVF with ICSI. The research findings are inconsistent across various studies, but some studies suggest a slightly elevated risk for imprinting disorders in ART-conceived individuals. lx,lxi,lxii It is important to note that these risks are still exceptionally low.lxiii,lxiv
It is also important to note that any potential effects of IVF on epigenetics discussed in this section are not specific to the use of donor eggs, as these would apply to using own eggs, or donor embryos.
What traits can a birth mother pass on to her donor-conceived child?
In the case of donor egg- or donor-embryo-conceived children, the traits a birth mother can pass on are nuanced. While physical similarities may arise from donor selection based on shared characteristics, there is no scientific evidence that heritable traits such as eye color, hair color, or height potential, among others, can be transferred from the birth mother carrying the baby. Often the donor-conceived child will resemble the intended parent based on selecting a donor with similar characteristics – for some parents this is important, for others it has no importance, and all approaches are valid. Resemblance may also result from shared mannerisms, shared qualities, and/or the influence of the parenting environment, rather than genetic inheritance.
While the birth mother of donor-conceived offspring does not share their children’s genetic code, they do influence embryo and fetal growth.lxv As discussed above, mechanisms such as epigenetics and the overall health of the uterine environment contribute significantly to shaping the child’s development. Epigenetics highlights how environmental factors can impact gene expression, potentially influencing the future child's health and well-being.lxvi
Conclusion
The interplay of genetics and environment in the context of epigenetics and donor-conceived children is complex. It is useful to understand the concept of epigenetic changes during embryonic and fetal development. While physical traits are not directly inherited from the donor egg recipient, the birth mother's role in shaping development through epigenetic mechanisms is one way in which they contribute to the child’s development. Using donor eggs or donor embryos can be a sensitive issue, and it is important to appreciate that a parent’s contribution to their child’s development extends vastly beyond the child’s DNA sequence.
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iii Dvoran, M., et al. (2022). An Interplay between Epigenetics and Translation in Oocyte Maturation and Embryo Development: Assisted Reproduction Perspective. Biomedicines, 10(7), 1689–1689. https://doi.org/10.3390/biomedicines10071689
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lxiii Henningsen, A. A., et al. (2020). Imprinting disorders in children born after ART: a Nordic study from the CoNARTaS group. Human reproduction (Oxford, England), 35(5), 1178–1184. https://doi.org/10.1093/humrep/deaa039
lxiv Kitsiou-Tzeli, S., & Tzetis, M. (2017). Maternal epigenetics and fetal and neonatal growth. Current Opinion in Endocrinology, Diabetes and Obesity, 24(1), 43–46. https://doi.org/10.1097/med.0000000000000305
lxv Kitsiou-Tzeli, S., & Tzetis, M. (2017). Maternal epigenetics and fetal and neonatal growth. Current Opinion in Endocrinology, Diabetes and Obesity, 24(1), 43–46. https://doi.org/10.1097/med.0000000000000305
