Infertility and Epigenetics- What are the implications for IVF and assisted reproduction?

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Epigenetic Mechanisms in Eggs and Sperm

Heather Huhman invited me to discuss epigenetics and infertility for the Beat Infertility Podcast. Below is a transcript, edited a bit for clarity and expanded in some sections. Join the conversation by liking ART Compass on Facebook.

What is epigenetics, and how does it differ from genetics?

I’m going to use one long analogy but, I want to flip the question and ask it this way “What is genetics and how does epigenetics differ from genetics?”

Starting with the very basics, your genome is an encyclopedia of cookbooks. Each cookbook is a chromosome, and each gene is a recipe contained in that book. You only have 23 volumes in this encyclopedia. But, you have two copies of every single cookbook.

One that was passed on to you by your mother and one that came from your father’s side of the family. The recipes contained in the books are essentially the same, except they contain small modifications in flavor, texture, and timing. When there is a LARGE difference, lets say your mother’s recipe calls for chicken and your father’s recipe calls for beef, then you have a mutation. Mutations can be good, the recipe tastes even better, bad like a disease state, or neutral- no change is detected by the taste tester. In biology, what the recipe produces inside your body is a protein. Our recipes are spelled of an alphabet that contains just four letter ATC and G. Those letters are read in words in groups of three. These three letter group produce all of our amino acids. You hear a lot about an amino acid called tryptophan around thanksgiving — supposedly it makes you sleepy. When a string of amino acids is put together they make enzymes, muscles, hormones and nearly everything else that make up our bodies.

That is genetics. Epigenetics is those small tiny differences to the recipe that change its flavor, texture, or timing. These changes are both inherited from your parents, but also further tinkered with by you; your diet, your environment and exposure to chemicals, stress and more.

Why is epigenetics important?

Epigenetics is how each cell starts off exactly the same in an embryo, and each cell keeps ALL of the DNA it starts off with throughout your life, but becomes differentiated into hearts, lungs, ovaries, sperm and your brain.

Epigenetics is how the next generation know which set of 23 cookbooks came from which parent. Farmers and animal handlers have known for a long time that you can breed two close species, for example a lion and a tiger but depending on which species each parent is you get a different outcome- in this case one cross produces a tigon and the other a ligar.

Epigenetics is important because it means that not every control mechanism for gene expression needs to be in a hard code, spelled inside the DNA itself. It allows the transmission of a message to our future generations about the world we are experiencing. Epigenetics allows genome flexibility based directly on the environment around you, and that can be either a good thing or a bad thing. If your grand and great-parents experience hardship, like many of ours have had through the great depression, multiple world wars, radiation testing and more. Their instructions to the next generation may be to create smaller offspring who use up less resources and are more likely to survive hard times. But, on the flip side if resources become abundant those children may hoard resources during their lifetimes and experience obesity, cardiovascular disease, type two diabetes, cancer and more as a result.

How has the study of epigenetics evolved over the years?

The structure and function of DNA was just discovered in 1953. Epigenetics had a broad and imprecise meaning in those days, although it was known term relating breeding to development. As we learned more, the human genome was sequenced completely in 2003, we started to refine that definition to what it means now, essentially to mean heritable changes to DNA expression that are not written in the DNA recipe itself. We’ll discuss more about the ways the body accomplishes this a bit later. If you consider that scientists act like chefs in the lab, transcribing and translating those recipes, and studying the proteins that are produced, we have only been able to do this for such a short fraction of time. We are learning new genetic AND epigenetic mechanisms everyday, and it will take many lifetimes to fully understand the human genome, if it can ever be fully understood. I’m not sure if it can ever be completely known to science.

· What are epigenetic changes? Can they be inherited, or is the impact more on an individual level?

They are both inherited from your parents in a stable way, but also capable of change in response to the environmental conditions you experience.

· What is DNA methylation?

DNA Methylation is the most well-studied epigenetic mechanism. A methylation mark is a rather simple chemical unit made of one carbon atom bonded to three hydrogen atoms. Carbon, is the basis of all organic life. It is an amazing molecule because it can form four chemical bonds to other atoms, and because the carbon atom is just the right, small size to fit in comfortably as part of very large molecule- like DNA! DNA is a twisted ladder and it has major and minor grooves that run up and down its whole lengths. Those methyl group which you may see written in shorthand as CH3, grab onto a fourth location on the DNA, fitting right on top of it into those grooves. Their signal to bind DNA is when they come across multiple C and G letters that are grouped together. If there are a lot of methyl groups it prevents the recipe from being read — ie no protein is made. Stripping those methyl groups off allows the sudden expression of that gene! Suddenly there is dinner where before there was none.

· What is non-coding RNA-associated gene silencing?

If you consider DNA to be the original, handwritten recipe passed down direct from your grandmother, you know you are not going to lend that precious document to Aunt Sally who wants to make that special dessert. You make a copy of that recipe, and keep the original safe and sound. Your cells do that same thing, before DNA can make a protein it goes through a copy step, that is called transcription of the DNA into a very similar molecule called RNA. Normally, the RNA makes its journey through the rough endoplasmic reticulum a tiny organelle that translates the RNA into a protein by reading those amino acid sequences and stitching them all together the right way. In the case of RNA gene silencing the RNA, which is very similar to DNA finds a sequence that has all it’s best friends in it and they shake hands. What I mean by that, is A is always friends with T and G is always friends with C. They form chemical bonds between each other. So, the non-coding (meaning it is not a recipe for a protein) RNA finds its corresponding best friend sequence on the DNA, it binds to it, and again, physically blocks the further action of that piece of DNA.

· What is histone modification and chromatin remodeling?

DNA exists is long goopy strands prone to tangling, breaking etc. most of the time the DNA is floating around free in the cytoplasm of your cells, but when it comes time for cell division, that DNA needs to get whipped into SHAPE. It gets wound around proteins called histones, like winding a bobbin thread, and packaged up into the typical chromosome that you can see in your mind’s eye as an X shape, or sometimes a Y shape. DNA has a negative charge, so it attracts positive things to it. Histones have positive charges. The when the DNA is wound into chromosomes it is called chromatin. And those packages of chromatin are not open for any action. Packages are good for carrying, and right after DNA is replicated that is when it gets packaged up and carried over to opposite sides of the cell, then the cell splits in two and you have cell division. In epigenetic regulatory situations you have varying degrees of control of these histones. You might loosen up certain segments for action, or wind up others to shut them down.

How does epigenetics impact female fertility?

Reproduction and the transmission of genetic information from generation to generation really is ground zero for epigenetics.

Epigenetics’ regulate nearly every aspect of fertility, from the eggs and sperm cells that started forming when you were just a fetus, really just a tiny ball of cells, to the way blastocysts and embryos develop, to the future fertility of your offspring. Even mammary glands have an epigenetic memory. The eggs in your ovaries are a packet of DNA representing your half of the encyclopedias that you will pass on, and these were put on the bookshelf before you were even born.

All of the eggs that you have migrated to the site of your future ovary from the outermost layer (called the endoderm) of the embryo that developed into you! In women our eggs are resting in our ovaries until the follicle starts growing and the egg gets called upon to complete meiosis. Meiosis is the type of cell division that gives you half the number of chromosomes, unlike in the cells of your body that contain a complete set of encyclopedias.

Meiosis actually will not be complete until after the sperm penetrates the egg. Meanwhile, as the egg grows and changes and undergoes this meiosis, epigenetics is playing a part. We are starting to become older and older, as a population by the time we want to start building families. Maternal age, environmental stress like pollution and household cleaning products, BPAs and plastics, diet / lifestyle like smoking and alcohol, and probably meat consumption probably all play a role in egg quality, as well as the lot you inherited from your parents.

· How does epigenetics impact male fertility?

In much the same way that it affects female fertility, with one or two large exceptions. Sperm are constantly being produced fresh from stem cells in the testicles. Unlike in women, where our eggs have been waiting on the shelf since we were born. But, sperm also have no cellular protection around their DNA. The sperm is basically reduced to a tiny DNA missile, with only one real purpose in life. Find the egg and deliver the encyclopedias. The egg has multiple roles, it contains all of the nutrients, factors, and protection the developing embryo needs.

· Do fertility treatments impact epigenetics? If so, how?

I have seen a lot of diet and lifestyle advice and supplementation recommendations that in general are good for DNA replication and soaking up free radicals that can damage DNA. Folic acid is well know to have real and long lasting positive effects on DNA, Co Enzyme Q is a very interesting supplement that is being studied and Vitamin D depletion seems to have a suspected effect on DNA methylation. The best advice is to be mindful of your health, stressors, intakes and more for years before you hope to conceive. Sperm grow on a three month cycle and eggs much longer (perhaps even a year before the egg is ovulation).

Assisted reproduction procedures are performed at a time when many important epigenetic reprogramming events are occurring in the gametes and embryos, yet the extent of these epigenetic changes and the relevance to human health and disease in assisted reproduction is only just beginning to be understood.

In humans there are a number of congenital disorders, termed imprinting disorders (IDs), caused by the disruption of imprinted genes, including Beckwith‐Wiedemann syndrome (BWS), Silver‐Russell syndrome (SRS), and Angelman syndrome (AS). Of these, BWS and SRS appear to be associated with assisted reproduction.

Several studies have indicated that ARTs are associated with fetal growth restriction, prematurity, low birthweight for gestational age, and slightly increased risk of cardiovascular malformations. Systemic and pulmonary vascular dysfunction and right ventricular dysfunction have been observed in children and adolescents conceived through ART. Assisted reproduction pregnancies have also been associated with larger placentas and higher placental weight/birthweight ratios.

· Is there a way to test for epigenetic markers?

Abnormal methylation of CpG dinucleotides has been shown in numerous studies to be found in infertility patients with oligozoospermia.

One of the most intriguing implications of the understanding of the sperm epigenome is the potential of it being the major link between environmental influences and altered fertility. The epigenome is influenced by environment, including age, diet, exposures and medicines and supplements. Sperm DNA methylation changes occur during paternal ageing, so simply freezing sperm while you are a young man for later use could be helpful as our population waits longer and longer to have children. There are claims of sperm tests for epigenetic markers, however I have not seen these widely used clinically.

· Tell us about some recent epigenetics research related to fertility.

One of the most recent pieces of research that I am the most excited is not actually directly tied to epigenetics- yet- but I suspect it will be! Recently, scientists demonstrated that if your mother had high AMH levels when she was pregnant with you, and you have PCOS that could be the cause. PCOS is a full-blown hormone disorder. But much about PCOS remains mysterious even after decades of research, and despite the fact that millions of women have it and that it’s a leading cause of infertility. Even its name can be confusing, since PCOS may not always lead to the ovarian cysts. There is exciting work being performed about the regulation of the AMH gene, methylation, the quality of oocytes, and the prevalence of PCOS.

· What are some questions related to epigenetics and fertility that still need answers? Do you have a sense for when those answers might be possible?

Currently, it is not possible to assess the epigenetic status of the human preimplantation embryo during routine assisted reproductive technology (ART). We don’t know;

  • whether epigenetic defects exist unequivocally in ART‐derived embryos, and
  • what effects any putative ART‐induced epigenetic changes will have upon the growth, development and health of the baby.

Other areas topics I think are ripe for epigenetic mechanisms, investigations and possible treatments are; premature aging of oocyte in very young women, oocyte and ovary preservation in children undergoing cancer treatments, and babies made from two female cells or two male cells to give LGBTQ individuals their own fully biological children.

· Is there anything else you’d like to add about epigenetics research?

There will be many new exciting discoveries in epigenetics for many YEARS to some. Encourage your girls to go into science and start solving some of these problems!

About ART Compass

ART Compass is a plug in for existing EMRs that modernizes the technology IVF practices use to manage laboratory quality requirements, statistical analysis and patient tissue inventories.

ART Compass is an essential tool for; evaluating the introduction of a technique or process in the IVF Lab; recording proficiency via customized surveys to evaluate clinical decision making; monitoring ongoing performance within a QMS (for internal quality control (IQC), external quality assurance (EQA)); benchmarking and quality improvement.

Dr. Carol Lynn Curchoe, Founder ART Compass

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