Exposure to substance abuse in the womb: Is it linked to adverse health effects during adult life?

In an earlier post we commented briefly on how early-life exposure to substances such as alcohol, tobacco, cocaine, and heroin can increase the chances of birth defects. The question we intend to answer now is whether this kind of exposure has long-term health effects. A review published in 2013 by A.M. Vaiserman summarizes the research on this subject. The author concluded that substance abuse by a mother not only affects her child's health around the time of birth, but also causes adverse effects that are long-term and are established by epigenetic mechanisms.

Epigenetic regulation, which includes the mechanisms discussed in the linked post, has been shown to have an important role in the programming of late-onset pathologies, including type-2 diabetes, neurodegenerative diseases, and cancer. Substance abuse during pregnancy can affect the programming occurring in the developing embryo or fetus, and consequently increase the chance of pathology. There are currently more findings about the effects of prenatal substance abuse on the health outcome of the infant than on the adult. However, research on this area is increasing and yielding interesting results that link prenatal substance abuse with more long-term health consequences than what was known before.

Developmental impairments induced by prenatal exposure to substance abuse

Imagine a world where each living individual upholds the secrets of past generations. This world is not a pop up from a fiction novel, but rather the reality of many organisms whose genetic expression is orchestrated and fine tuned by an epigenetic machinery. Recent scientific breakthroughs have discouraged the traditional belief that the epigenome is of a stagnant nature, and have thus progressed the idea that the machinery’s multiple modifications are dynamic as well as susceptible to environmental outcomes. 

The human epigenome is particularly sensitive to secondary, nonnormative environmental factors such as early exposure to psychoactive substances (alcohol, smoke, tobacco, cocaine, etc.)  that can drive epigenetic changes in gametes, consequently prolonging the effects of the exposure beyond the current generation and into future, unexposed generations. The most profound influence on epigenetic states occurs during prenatal life, more specifically during gametogenesis and embryogenesis, where progressive waves of genome-wide demethylation and re-methylation increase genetic/environmental stimuli vulnerability and result in the potential acquirement or deletion of epigenetic markings that can stimulate both short or long term effects on fetal programming via mechanisms of epigenetic memory. Substance abuse during pregnancy interferes with the normal epigenetic machinery, triggering a series of impairments in crucial environmental inputs of fetal programming such as the placenta, uterine tissue, offspring-mother hormonal balance, and proper maternal blood supply. 

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Alcohol exposure can severely impair human physical and neurobehavioral development with the obstruction of epigenetic markings potentially directing organ development, hormonal balance, and normal metabolic development. Prenatal exposure to alcohol has also been linked to aberrant genetic expression induced by alterations in genes controlling methylation, chromatin remodeling and protein synthesis, including histone hyperacetylation, hypermethylation in genes controlling metabolic pathways, and hypomethylation in genes associated with development, genomic imprinting and chromatin remodeling. Nicotine intake has been associated with pulmonary malformation and metabolic syndromes such as obesity, high blood pressure, and altered glucose homeostasis including a resistance to insulin both in the first and second generation offspring. Prenatal tobacco exposure can potentially influence global and gene-specific DNA methylation by targeting imprints in males. Smoking is also believed to alter brain plasticity and proper neurological development through promoter methylation in genes crucial for brain development such as BDNF, and has further been linked to neurotransmitter impairment in the fetal heart. Cannabis is also believed to cause neurotransmitter impairment, specifically by decreasing the expression of DRD2 (dopamine receptor D2) mRNA in the brain, increasing addiction vulnerability in the growing fetus. On the other hand, exposure to illicit drugs such as cocaine, heroin and amphetamine has of late been associated with the development of malignant neoplasms and heart dysfunction leading to shorter lifespans. 

Although DNA methylation remains the most studied epigenetic mechanism underlying substance-exposure diseases, it is by no means the sole contributor. Substance abuse has shown to trigger multiple epigenetic pathways, with most inducing an overall gene downregulation. Therefore, determining which epigenetic regulators are vital participants and stressors in prenatal development would help improve pregnancy outcomes via the potential control of diseases and undesirable complications.

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Bibliography 

Vaiserman, A. M. (2013). Long-term health consequences of early-life exposure to substance abuse: an epigenetic perspective. Journal of Developmental Origins of Health and Disease, 4(4), 269–279. doi:10.1017/S2040174413000123

Pregnancy and Substance Abuse

Substance abuse is a worldwide problem that affects many people, regardless of societal level, gender and age. As defined by the World Health Organization it's the use of harmful psychoactive substances - be it drugs or alcohol - that can lead to a dependency or strong desire to take the drug without concern of consequences. Some of the most commonly abused substances include alcohol, cocaine, heroin and tabacco. One major problem is the use of these controlled substances during pregnancy. It's been shown that using certain drugs in this time period significantly increases the chances for birth defects, premature babies, underweight babies and still born births. This outcome lies on the fact that almost all drugs are known to cross the placenta and have some degree of effect upon the fetus. The effects of an array of drugs on the development of babies have been studied since the 1960's with the cigarette. Prenatal smoke exposure has been linked to increased risk for diseases, poor psychological and developmental outcomes, reduced birth weight and behavioral disorders later in life. A difficulty in predicting and establishing potential side effects of drugs on the fetus is due to the fact that the effect will depend on the time of pregnancy, dosage, and route of the drug.

 

In the following blog posts it will be reviewed and informed some of the ways it's been shown that substance abuse during pregnancy affects the epigenetics of fetal development that leads to some of the outcomes mentioned above.

 

 

X chromosome inactivation: How does it work?

In the previous post, it is discussed on how DNA can be modified and can change depending on external situations and how different combinations of factors can modify the genetic code. But it is imperative to discuss the main location of one of the central coding for mammals, and especially humans, and those are the chromosomes. Chromosomes as we know are very tight packets of DNA that contain the major building blocks of any organism. The chromosomes are then long strands of DNA that when combined can form any and all of the organisms in this world. But one chromosome in particular is very indicative to the creation of the organism in mammals, including humans, are the parent chromosomes, which in turn are the X chromosomes for mother, and Y chromosomes for the father. Within these chromosomes, it’s not surprising that the X chromosomes are the more important part of the pair, since it allows half of the set needed to form the embryo.

But it’s not as simple as it sounds. While it is commonly known that, when both chromosomes combine thanks to the sperm cells and the oocytes, both form the zygote that would replicate into a fetus, but there is also another step that is crucial for the genetic maintenance of the embryo, and that is X chromosome inactivation. Now, while it sounds redundant, it’s actually a very important process in the early stages of gestation of the zygote. X and Y chromosomes are crucial in the development of the sex of the fetus, since XX is for female and XY is for male. This is common knowledge, but there is more to it. In females, there has to be the process known as X chromosome inactivation.  In XCI, is creates a cellular complex that silences any excess genes, and since females have 2 X chromosomes, its highly important to “inactivate” the second chromosome in order to avoid any problems during the early stages of replication. In order to do that, it uses XIST (X inactivating specific transcript) in RNA to regulate the inactivation and maintain order within the transcription and replication process. The use of XIST in various sequences along the inactive X chromosome creates a series of epigenetic modifications that result in the formation of facultative heterochromatin. This chromatin then causes epigenetic modifications like histone modification and the previously mentioned DNA methylation. All this happens in the later stages in development of the zygote before the formation of the full fetus. And it’s important to note that, when it comes to males, there’s transcriptional silencing of the X chromosome which leads to the formation of the XY compound during late meiosis.

So, now that we know what it does and why its highly important, it’s easy to understand how this process is needed to avoid any genetic mishaps or deficiencies during the gestation period, due to not only existing genetic deficiencies that may cause syndromes due to no regulation (Klinefelter syndrome or Triple x syndrome) or have over regulation (Turner syndrome). These syndromes, already having some light genetic possibility, can be even further augmented by using and abusing drugs. These factors have been shown to increase these factors, and have been shown to increase a light change in the epigenetic effects and can cause further problems for their future young.

To further view these points, I recommend you read these papers that have studies on the most common recreational drugs and alcohol that show light on the subject:

·        X chromosome inactivation in women with alcoholism, by Manzardo AM, Henkhaus R, Hidaka B, Penick EC, Poje AB, Butler MG, retrievable here: https://www.ncbi.nlm.nih.gov/pubmed/22375556

·        X chromosome inactivation in Opioid Addicted Women, by Vousooghi N, Shirazi MS, Goodarzi A², Abharian PH, Zarrindast MR, retrievable here: https://www.ncbi.nlm.nih.gov/pubmed/26904175

And as always, please stay tuned to this blog to further your understanding of your genetic code, and you! 

The epigenome and its modifications

As you might have read in an earlier post, the epigenome is composed of chemical markers that affect gene expression. These mechanisms do not alter a DNA molecule's nucleotide sequence, but they do affect the arrangement of chromatin (which is the complex of DNA, protein and RNA found in the nucleus) and accessibility to genes. An important function of chromatin is to pack DNA to a small volume, but it is also involved in gene expression.

Epigenetic modifications can be temporal, reversible, heritable, and affected by environmental factors. A common type of modification is DNA methylation, which is the addition of a methyl group to the nucleic acid cytosine found in DNA. DNA methylation is associated with gene silencing. In other words, this modification is commonly found in genes that are not being actively transcribed.

A very important category of epigenetic modifications is the histone tail modification. These modifications include methylation, acetylation, phosphorylation, ubiquitination, and SUMOylation. This list may seem overwhelming, but these are all simply additions of groups to specific residues (amino acids) found in the tails of the histone proteins that wrap DNA to form the chromatin structure. While acetylation, methylation, and phosphorylation involve the addition of relatively small groups, ubiquitination and SUMOylation add proteins, which are much larger.

Both DNA methylation and the modification of histone tails play important roles in gene expression, and the consequences of certain patterns have already been studied. Scientists are trying to uncover the mechanisms by which these modifications and their specific combinations affect gene expression. They are also interested in how these modifications occur and which are their triggers. This blog focuses on findings about the relationship between substance abuse by a woman and modifications to her fetus' epigenome. If you are interested in learning more about this fascinating subject, make sure to check in weekly!