How can epigenetic changes affect your fertility or the health of your child conceived by fertility treatment? We talk with Dr. Jason Franasiak, a board certified Obstetrician Gynecologist, board certified Reproductive Endocrinology and Infertility specialist, board certified High Complexity Laboratory Director in Embryology and Andrology, and lead physician of RMA’s Marlton Clinic and Lab in South Jersey. He has authored and contributed to over 100 peer reviewed publications, published chapters and abstracts. He serves on the Editorial Board for Fertility and Sterility and the British Journal of Obstetrics and Gynecology.
In this episode, we cover:
This podcast is produced by www.CreatingaFamily.org. We are a national non-profit with the mission to strengthen and inspire adoptive, foster & kinship parents and the professionals who support them. Creating a Family brings you the following trauma-informed, expert-based content:
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How can epigenetic changes affect your fertility or the health of your child conceived by fertility treatment? We talk with Dr. Jason Franasiak, a board certified Obstetrician Gynecologist, board certified Reproductive Endocrinology and Infertility specialist, board certified High Complexity Laboratory Director in Embryology and Andrology, and lead physician of RMA’s Marlton Clinic and Lab in South Jersey. He has authored and contributed to over 100 peer reviewed publications, published chapters and abstracts. He serves on the Editorial Board for Fertility and Sterility and the British Journal of Obstetrics and Gynecology.
In this episode, we cover:
This podcast is produced by www.CreatingaFamily.org. We are a national non-profit with the mission to strengthen and inspire adoptive, foster & kinship parents and the professionals who support them. Creating a Family brings you the following trauma-informed, expert-based content:
Please leave us a rating or review RateThisPodcast.com/creatingafamily
Please leave us a rating or review RateThisPodcast.com/creatingafamily
Please pardon the errors, this is an automatic transcription.
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Welcome, everyone to Creating a Family talk about infertility. I'm Dawn Davenport. I am the host of this show as well as the director of the nonprofit creating a family.org. Today we're going to be talking about epigenetics and fertility and infertility treatment. We'll be talking with Dr. Jason Franasiak. He is a board certified obstetrician gynecologist and a board certified reproductive endocrinologist and infertility specialist. He is also a board certified high complexity laboratory director in embryology and Andrology. He is the lead physician of RMA Martin's clinic and lab in South Jersey. He authored and contributed to over 100 peer reviewed publications, published chapters and abstracts. He serves on the editorial board for fertility and sterility and the British Journal of Obstetrics and Gynecology. Welcome Dr. Franasiak to Creating a Family. Dawn, thank you so much for that very kind introduction. It is such a pleasure to be back on the podcast. It is a pleasure to have you back. I think we need to start at the beginning, which is always a good place to begin. Think there's actually a song associated with that from the sound of music, isn't it? Anyway, we should start at the beginning, which is what is epigenetics? Well, it's on I think the beginning is a great place to start. I think it goes without saying that your genes play an important role in your health, but so do your behaviors in the environment, such as what you eat and how physically active you are. So epigenetics is the study of how behaviors and environment can cause changes that affect the way your genes are your DNA works. So unlike genetic changes, epigenetic changes are reversible, and don't change your DNA sequence. But they can change the way your body reads a DNA sequence. So gene expression refers to how often or when proteins are created from the instructions within your genes. So while genetic changes can alter which protein is made, epigenetic changes can affect gene expression to turn genes on or off. Since your environment and behaviors such as diet and exercise can result in epigenetic changes. We can therefore see it's that easy kind of connection between your genes and your behaviors and environment. Okay, well, that leads to the question of what factors can influence or affect the epigenome? Well, you know, I think that there are a couple of different things actually. So factors which impact epigenetic start even before you're born, aging and environmental factors can also influence the epigenome. So a couple of things to kind of review here. In terms of epigenetics and development, we noted that epigenetic changes begin before you're born. We think about this, all of the cells have the same genes in your body, but they all look and act very different. You grow and develop, epigenetics will determine which function a cell will have. So for example, if it becomes a heart or a nerve or a skin cell. So if we take the example of nerve versus muscle cell, the muscle cells and nerve cells, again, they have the same DNA, but they work differently. a nerve cell transports information to other cells in the body, a muscle cell as the structure that aids in your abilities, your body's ability to move. So epigenetics allows the muscle cell to turn on genes and proteins that make proteins do a job and turn off genes which are important to a nerve cells job in terms of epigenetics and age. So epigenetics changed throughout life, the epigenetics of birth, not the same as the epigenetics in childhood or adulthood. There was a study that was done that looked at DNA methylation, which is a form of epigenetics that we'll talk about in a moment. And it was found that in the DNA methylation sites in a 26 year old versus 103 year old were very different DNA methylation in the newborn was the highest and in the 103 year old, it was the lowest in terms of epigenetics and reversibility. Not all epigenetic changes are permanent, as can be seen, for example, with smoking. So there are certain parts of a gene called the ah RRG, which has been linked to lung cancer smokers tend to have less DNA methylation than non smokers and
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The difference is greater for heavy smokers in long term smokers. And we can actually see the reverse of this when smoking cessation occurs. Hmm. So okay, so age can affect the epigenetics. Smoking can affect epigenetics can obesity, obesity certainly can impact genetics. So we do know that our environment, what we take into our bodies, the types of foods, smoking, and then our levels of exercise, all of these things do impact the epigenome.
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Interesting. And so how do epigenetic factors you've alluded to this affect our general health? We're going to be talking about fertility in a minute. But just in general, how do epigenetic factors affect our health? You've mentioned the lung cancer being impacted by the lung factor a gene associated with lung factor, lung cancer being impacted? Are there other ways that epigenetic factors can impact our health? Yes on there are, there are a couple of examples that I can kind of review. One of them are infections. So germs can actually change epigenetics, which actually can weaken our immune system and help the germs survive. So an example of this would be mycobacterium tuberculosis, which causes tuberculosis. So infections with these germs can lead to changes in histones, and those are the proteins that DNA is wrapped around. And if the DNA is wrapped around the histone tightly, it can turn genes off and if it's wrapped more loosely, it could turn genes upon and it the tuberculosis can cause changes to these histones, which turn off some genes which weakens our immune systems and improves the survival of tuberculosis. Similarly, cancer is another area of of interest. We talked about lung cancer, but there are other types of cancers. So for example, the BRCA one gene, it is very well characterized in terms of breast cancer and other cancers as well. However, increase DNA methylation and epigenetic change can result in decreased BRCA one gene expression which raises the risk for breast cancers and other cancers. An interesting thing I don't know if some folks have seen on TV of late there is a commercial colorectal screening tool, which utilizes stool samples which are sent in so what this study actually does is look at DNA methylation sites at certain areas of the DNA in the stool, it's been shown that there are abnormal methylation sites at certain areas in the genome, which causes colorectal cancer. Now, obviously, if you have a positive test, you need a colonoscopy to more formally diagnosis. But it's an interesting area where the epigenome is being harnessed and utilized in a diagnostic test. And I think that maybe for this particular podcast in general, the one of the final areas that I think is a very interesting area on how epigenetics impacts our health is nutrition during pregnancy. So a pregnant woman's environment and behavior during pregnancy, such as whether she eats healthy food or not, can change, AB epigenetics. And some of these changes can remain for decades and may make the child more likely to get certain diseases. A very famous example of this is the Dutch hunger, winter famine from 1944 to 1945. And individuals whose mothers were pregnant with him during the famine, are more likely to develop certain diseases such as heart disease, schizophrenia, and type two diabetes. Around 60 years after the famine, researchers looked at methylation levels and people whose mothers were pregnant with them during the famine. And people had increased methylation, again, an epigenetic change at some genes and decrease methylation and other genes compared to their siblings who were not exposed to the famine before birth. And these differences in methylation could explain why these individuals have increased likelihood of certain diseases later in life. Okay, so maybe it's now time to talk about DNA methylation.
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That that is one way that epigenetics can be expressed that you can call It's a change or the epigenetics. epigenome can cause a change in gene expression. So what is DNA methylation?
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That's a great
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Question. So there are a couple of different epigenetic changes which can be seen looking in the laboratory and a couple of different areas. DNA methylation is one of them. So DNA methylation works by adding a chemical group to DNA. This group is typically added in specific places where it blocks proteins that attached the DNA to read the gene, this chemical group can be removed through a process called D methylation, and typically methylation turns genes off, whereas D methylation turns them on. Okay, that's because the, what the the, the D part the that's preventing the reading the methylation is preventing the reading of the gene. So if you take it off you d mentalize. It then it becomes you can read the gene. Okay, that's exactly right on. So that's the, that's the epigenetic impact of methylation. I did briefly talk about one of the other forms of commonly known epigenetic changes, and that's histone modification. So DNA wraps around proteins called histones. So DNA wrapped tightly around these histone proteins can't be accessed by the proteins that read the G. So some genes are wrapped around histones and are kind of turned off, they aren't able to be expressed, whereas DNA that's not wrapped around histones tightly is turned on. And there can be factors which modify these histones. And so DNA methylation is one form of epigenetic changes. histone modification is another form. And then one of the final forms done is non coding RNAs. So I know that I don't want to get too technical for for all of our listeners here. But in general, your DNA, the genes is used to make both coding and non coding RNAs. So in the way that our bodies worked are kind of blueprints we had DNA, and that DNA turns into RNA. And that RNA turns into proteins. And proteins are kind of what do all of the work with coding RNAs, those coding RNAs are used to make proteins. non coding RNAs are a component of epigenetics. So non coding RNAs help control gene expression by attaching to the coding RNAs and turning the coding RNAs on and off. Does that make sense? Yeah, well of source Yes, it does. Actually, no, it does make sense. And all of these now, all of these changes that are made through any of the a number of factors B they diet to be the obesity be they smoking or whatever they are, all the causes, that all the impacts, the things that can impact our epigenome. Those changes are their heritable, meaning that the child was going back to the study of the feminine and during World War Two were the children I'm sure that were stood the children of the people who were impacted the fetuses, the babies who were born during that famine time, their children have been I know they have been studied as well, were the epigenetic changes and the impacts the health impacts that affected their parent who was in utero during the famine, did a pass on to the children. So you know, Assuredly, we can see with the Dutch hunger, winter famine that when a mother is impacted by her environment, it can change the epigenome of her child that she's currently carrying, and those epigenetic changes can persist. And we would suspect that those epigenetic changes can be again transmitted to their children. One of the things that is very interesting is that during very early development, there is a fairly significant component of D methylation and then re methylation that occurs. So it may not be fully transmitted from generation to generation, but we can see the impact of these across generations from a specific event as was mentioned with the Dutch winter famine, interesting.
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To subscribe, you could scroll through our archives and listen to even more topics related to today's show on epigenetics.
15:09
All right, now let's shift to talking about the genetic and epigenetic factors associated with different types of fertility. We're going to start with female infertility. Let's go ahead. So what are some of the epigenetic or genetic factors associated with female fertility, let's say or infertility either? Sure, well, in general, there are several genetic issues which can cause female infertility. So some of these include karyotype issues. So karyotype is looking at all of your DNA and whether or not you have missing or extra whole chromosomes. So for example, women that have a missing sex chromosome as in Turner Syndrome, it can result in ovarian insufficiency and also as implications for pregnancy given cardiovascular risk factors. There are genetic issues related to ovarian reserve with fragile X primary ovarian insufficiency, and that's a genetic mutation with repeated C, G, G. Those are nucleotides or portions, building blocks of DNA, so repeated portions of those in the X chromosome. And there are also mutations such as congenital adrenal hyperplasia, which can cause imbalances in hormones produced by the adrenal glands and causes menstrual irregularities, which can actually mimic polycystic ovarian syndrome or PCOS. There are issues with chromosomal rearrangements. That's where the mother has the correct amount of DNA, but it's in an abnormal orientation. So just that when it goes from a whole set of DNA to a half set of DNA to combine with sperm, the other half of the DNA, it can reliably increase the likelihood that an embryo will have an unbalanced amount of DNA and increase the chance of miscarriage or birth defects if a child being born with birth defects, right, absolutely. Okay, so those are genetic factors that can influence that's something that's with the DNA itself. What about epigenetics, which is affecting the expression of the DNA? Are there epigenetic factors that affect female fertility? So it's a very interesting area of active research on so we know that as women age, the epigenetics change, and there have been some studies which have looked at the impact of epigenetics on ovaries and oh sites, there is really actually much more data on epigenetics of spermatogenesis. One of the things to think about is that oh sites are quiescent, meaning that they are not active actively dividing until the follicle develops receptors to respond to gonadotropins. So much of their DNA is very tightly bound and kind of locked away. So there is not as much in the way of epigenetic studies on eggs and ovaries as of yet but there is research being done. Interesting. Okay. So now, is there one of the main causes of female infertility or Oh, certainly a large one is PCOS. Is there an epigenetic connector to PCOS? Or let's talk genetics and then epigenetics. So, you know, it's really very interesting, you know, as we had already mentioned, there is the utilization which can cause congenital adrenal hyperplasia, which results in increase hormone production from the adrenal glands, and this can mimic PCOS and cause menstrual irregularity. So it's really important to rule this out whenever a diagnosis of PCOS is entertained. It is estimated that about 70% of PCOS is inherited. However, genes that are linked to PCOS so far account for really only about 10% of this heritability. So it's not something that in routine practice, we would ordered genetic panels to look at for PCOS. There is growing evidence that suggests that altered epigenetic programming resulting from hormonal dysregulation of the maternal uterine environment can contribute to the pathogenesis of PCOS. And that would be an epigenetic factor that was in utero, the fetus was being exposed to the hormones of the mom. That's exactly right, Don. Interesting. So, you know, again, male and female relatives of women with PCOS are at increased risk of developing PCOS associated reproductive and metabolic disorders. So
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There's certainly is a genetic and epigenetic component to PCOS. I don't know that any of this is ready for primetime in terms of diagnosis. But you know, I would say stay tuned with this makes me wonder, and this is, if there have been studies of women who have taken continue to take birth control for whatever reasons, usually, because they're unaware that they're pregnant. So they're continuing to take birth control. And it seems like those it would be interesting to study those children. And I think there have been some studies which were indicative that that it did not have a harmful impact. But perhaps they stopped too soon. The study said, would that be a way of studying it seems to me that you certainly have a different hormonal milieu going on if you're taking birth control through a pregnancy, potentially. So although I will say it's not likely that you would be able to be on birth control pills through the entirety of pregnancy. And my suspicion would be at some point, you would recognize that you were pregnant. And so it depends upon how long you were really on that. And then also the level of those hormones and how much of those hormones crossed the placenta and actually entered the developing fetus? I think it's a really interesting area of research. One of the things I don't know, Dawn is the number of people who have had that happen if there are enough of them in order to really do an adequate study. And how do you quite frankly, how do you find them? Because generally, as you point out, one would assume at, you know, three, four months at the most, you're going to have caught on and the fact that getting pregnant on birth control pills is not that common to begin with. So yeah, finding you're finding the number of participants in that study could be a challenge. I would agree. That makes sense. All right. Let's talk about endometriosis. Another common cause of female infertility, genetic and epigenetic factors that influence the development of endometriosis. Absolutely, so I mean, there is accumulating evidence that suggests that there are various epigenetic alterations which can contribute to endometriosis. One of them DNA methyl transferases, histone deacetylase Laters in noncoding, micro RNA. So that's all very scientific talk. But some of them we did talk about with acetylation of the histones are the alteration of histone proteins and non coding RNAs. There is difference in expression within the endometriosis lesions and the lining of the uterus in patients with endometriosis. So there actually are these epigenetic changes. The identification of these epigenetic differences within the DNA or the histone proteins, the proteins that the DNA is wrapped around, may contribute to the discovery of a useful test for disease prognosis in the future. It could lead to earlier detection and timely diagnosis, which is important within Dmitri osis. Because certainly people with very early stage endometriosis may not even recognize that they have it until it becomes quite severe and debilitating. And this could really initiate new approaches to even treatments of endometriosis and inform us about the effectiveness of treatments and the stage of the disease. So I think that that epigenetics for endometriosis is a really interesting area of research. Yeah, I would think so too. Now, you've talked a little bit about certain epigenetic impacts of our health. We're no genetic changes, I should say genetic changes that contribute to primary ovarian insufficiency. Are there epigenetic changes that would contribute to poi? Yeah, so as we discussed on you know, Turner Syndrome and fragile X mutation or pre mutation or genetic causes of diminished ovarian reserve or premature ovarian insufficiency. There are emerging studies with epigenetic factors, particularly with the non coding RNAs, which may impact the chance of premature ovarian insufficiency. Again, so much of epigenetics is a very exciting new field and there are many promises for biomarkers for diagnosis, perhaps even one day prevention of premature ovarian insufficiency or treatment. We're not quite there yet, but I do think that there are some studies which have shown that these non coding RNAs may impact premature ovarian insufficiency. Interesting. Let's move now to talk about male infertility. And as you mentioned, there is there appears to be at least in the literature, a lot more information known about the epigenetic changes that can influence negatively male fertility. Let's let's talk about male fertility. What do we know
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are both about the genetic and epigenetic. Sure. So you know, we'll start with the genetics because those are a little bit more established or unknown. So there are several genetic issues which impact male fertility. These can include karyotype abnormalities, which we've discussed. So for example, claim felters syndrome, in which a man has an extra X chromosome, so x x, y, and this leads to testosterone deficiency and sperm production issues. They can also have mutation and mutations in the CFTR gene, that's commonly a cause for cystic fibrosis. So men with cystic fibrosis can add issues which cause an impact on a portion of the male reproductive tract called the vas deferens, which causes issue with sperm transport. And then there are other things like Y chromosome micro deletions, which also causes sperm production issues, as we had noted on there have been several studies which have looked at sperm DNA methylation, and its impact on spermatogenesis and sperm parameters. There have been several candidate genes which have been identified in which D methylation or methylation has impact on spermatogenesis. So I think that there are some areas that in the male side that are a little bit further along. Once again, I don't think that we're ready for use in the clinical setting just yet. Are there? has anything been tied to what is causing the epigenetic changes that are impacting male fertility? Well, one of the things that we do know is that certainly environment and lifestyle factors do impact these things. So as noted, smoking certainly causes changes, which can predispose to cancer and there have been some good studies which have showed epigenetic changes there. We do know that smoking is a very known cause of spermatogenesis issues. And so one would think that perhaps that could be due to some of the epigenetic changes. And then once again, we've noted that other things like obesity have an impact on spermatogenesis. So I do think that some of these things are very much tied to epigenetics in the male reproductive system. Interesting.
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I want to pause now to thank our partners who have made this podcast possible. One is cryos international sperm and egg bank. They have been a partner of ours for quite some time, and we so appreciate their support. Prayas international sperm and egg bank is dedicated to providing a wide selection of high quality extensively screened frozen donor sperm and eggs from all races, ethnicities and phenotypes. They do this for both home insemination, as well as fertility treatment. Prayas International is the world's largest sperm bank and the first freestanding independent egg bank in the United States. Another partner is Reproductive Medicine Associates of New York. Reproductive Medicine Associates in New York is a full service Fertility Center specializing in in vitro fertilization, egg donation, egg and embryo freezing, LGBTQ plus family building, reproductive surgeries and male reproductive medicine. highly individualized patient care is offered through 13, reproductive endocrinologist and fertility specialists, as well as a urologist and a full support team.
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Okay, now I want to move to an area that I I personally find fascinating and directly related to infertility treatment, one of the most promising and certainly the reven most revolutionary of the forms of infertility treatment two that has been developed. And his result and has resulted in millions of children being born is in vitro fertilization have there and we are certainly changing the very earliest forms of the environment, the the image just from the from the get go, it has been changed, and in particular, in vitro meaning and in a petri dish of sorts. And the answer there has to be a medium that the embryos are bathed in and as they grow, what type of research first of all is being done on understanding the long term effects? And I'm speaking primarily of the epigenetic effects because I don't think we would think that they would affect the genetic impacts of a one two cell three cell embryo growing for the first what, six, eight days, well, not eight so much, but six days in this medium. I mean, it's a huge environment.
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sort of shift from, from what happens without, with what happens in natural conception. So let's talk some about what do we know about that? Sure. Well done you know since the birth of Louise Brown, which was the first baby conceived with in vitro fertilization, there have been more than 9 million children born worldwide through IVF IVF. Of course, as you are in vivo rather. So in vivo rather than in vitro fertilization occurs in the maternal abductor, the fallopian tube where there are unique physiologic conditions which go into the healthy development of the embryo. It's important to note that during embryogenesis, there is a major wave of epigenetic reprogramming. And this is crucial for the correct development of the embryo. Epigenetic reprogramming is susceptible to environmental changes. You know, as we had mentioned during IVF, controlled ovarian hyperstimulation, or giving medications to get multiple eggs to develop is performed. Fertilization is performed either via conventional insemination where eggs and sperm are just placed together or via interest, cytoplasmic, sperm injection or xe in the IVF, laboratory care is taken to replicate to the best of our ability, the physiologic conditions of the fallopian tube, which includes the pH, the temperature and the oxygen tension. In the last decade, as you'd mentioned, there have been concerns raised a low possible link between IVF and increased incidence of imprinting disorders, which is an epigenetic phenomenon. And one of the issues is that we can see that infertile patients transmitting some of these epigenetic changes to their offspring following IVF. I think one of the challenges in any of these studies which look at this is, it's difficult to say for certain if it is the results of the treatment employed during IVF, or if it is due to the patients who required the IVF treatment in first place. And I think that's really the most challenging area, there are studies, which I think are kind of looking at epigenetics of children conceived with IVF. And their sibling is not conceived with IVF. But those studies are really very early. And the number of patients in them is not very large at the present time.
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and enhance, yeah, how do you design a study where you're? And because you're, well, there certainly are the infertile women who are able to give birth either before or after two and so that we could do to have two siblings that you could compare, but the numbers wouldn't be large. Yeah, that's, that's really that is interesting. What is you mentioned that an imprinting disorder is a type of epigenetic disorder. We're going to talk in a minute about epigenetic disorders. But before that, you've just mentioned it, let's ask what are imprinting disorders? And how would how would we know they exist and a child can save through IVF or any job.
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So in general, kind of the imprinting really has to do with the methylation changes that occur with that kind of global DNA methylation and re methylation process. And, you know, I don't know that, again, would be able to know for certain if a child born as a imprinting disorder, specifically due to IVF, or due to the couple that required the IVF in order to conceive.
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Okay, and what would an imprinting disorder be something that we would it be, is there one that you can mention that we would have heard of? Sure, so in terms of some of the imprinting disorders, there are several which have been correlated with IVF treatments. So these will be things like Beckwith Wiedemann syndrome, Angelman syndrome, prader willi syndrome, and so we're Russell syndrome. Again, a lot of these major methylation dynamics take place during the cell development in the preimplantation stages of embryonic development, it is possible that IVF can prevent the proper erasure or removal of this methylation and reestablishment of the of the DNA methylation. Okay, while that is happening, what about more and more embryos are undergoing genetic testing, and who were just removing a few cells from a five day I guess three hours
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Five, most of them are five now. Right. But anyway, embryo which would is coming from the the cells that will eventually form the placenta is
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that also is a significant change. So make a significant change from what would happen in without IVF. So, are there any thoughts that that can result in? I don't know if that would be less epigenetic and or, or certainly not genetic, but certain less epigenetic and just more environmental. But how do we tease that out? Anyway? Are there any results of that that would could be tied to that? Could the genetic testing cause some type of epigenetic changes? Sure. So in general, as you have mentioned, genetic testing of embryos, by and large occurs at the blastocyst stage. So this is day five, six or seven of development at this point, that at that point in development, the blastocyst is comprised of several 100 cells. And the genetic testing requires somewhere on the order of five to eight cells in order to make the diagnosis. So typically, the proportion of cells removed is very low by comparison to the amount of cells that exists. Now, there have been a couple of studies which have looked at the impact of embryo biopsy. But really, in these cases, Don, what they look at is the ability of that embryo to create a child. And in the studies that have been done that have looked at this, they have not found that the embryo biopsy decreases at the blastocyst stage, I'll say at the cleavage stage. So the day three embryos, if seeing those embryos, you're removing one or two cells that are only a couple of cells, and that certainly can impact that embryos ability to create a child. But the studies that have looked at the blastocyst stage by MC have not shown a decrease in that embryos ability to create a child. That being said, there's a lot more as we've talked about here today that go into making us who we are. And there have not been any studies to my knowledge, which have looked at epigenetic changes due to embryo biopsy. Okay, that was my question. All right. So what are we have mentioned, referred to epigenetic disorders, what are epigenetic disorders?
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So in general, epigenetic disorders are a diseases which impact the epigenetic processes that we've discussed. So that has to do with DNA methylation, histone modification, and non coding RNAs, all of these epigenetic processes or epigenetic disorders result in a differential expression of DNA, so turning on and off genes, okay. And imprinting disorders is one of them, but there are other types. Are there other epigenetic disorders that we may have heard of? I think that the the ones that have really been largely associated with IVF, we've kind of discussed, there are other epigenetic disorders which exist but have not been tied to in vitro fertilization or fertility care. Gotcha. All right. Well, thank you so much, Dr. Jason Franasiak for talking with us today about epigenetics and fertility and infertility treatment.
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