February 2013 Archives

On February 25, 2013 the journal Proceedings of the National Academy of Sciences published an article by Michele Yeo and colleagues on BPA and how it could cause neurodevelopmental disorders. BPA (bisphenol A) is a chemical that has hormone like qualities similar to estrogen. It can be found in the plastic materials in the environment, which can 'leak' into edible items (like water from a water bottle). This ingestion can lead to health problems like cancer and reproductive disorders.

In this paper, they found that BPA can impair central nervous system development. They did experiments to try to figure our how BPA exposure can lead to this using rodents and human nerve cells.

First of all, the development of neurons occurs with chloride presence. When the neurons are developing, there are high levels of chloride, and when the levels drop, the neurons are able to mature. KCC2 is a chloride transport protein that aids in removal of the chloride. It is known that if the level of chloride is not removed, damage can occur to the developing neurons by damaging neural circuits and "preventing" migration of the nerve cells to the appropriate position in the brain.

When BPA exposure is elevated the Kcc2 gene is shut down leading to altered altered levels of chloride in the neurons. This gene is responsible for making KCC2 protein. If that protein can not be made, then chloride regulation will be in trouble with a delay in removal. It was found that MECP2, which is a protein involved in normal brain function could be responsible for shutting down Kcc2 gene. MECP2's abundance increases during exposure of BPA. MECP2 binds to Kcc2 and shuts down the gene.

An interesting finding is that female's neurons were more sensitive to BPA exposure compared to males males. Further studies will be needed to give answers for this interesting finding, and if some sex hormone receptors, like estrogen, are involved with the relation of BPA and KCC2.

In summary, BPA exposure is involved with normal neuron development by effecting Kcc2 gene regulation.

Literature Cited:
Michele Yeo, Ken Berglund, Michael Hanna, Junjie U. Guo, Jaya Kittur, Maria D. Torres, Joel Abramowitz, Jorge Busciglio, Yuan Gao, Lutz Birnbaumer, and Wolfgang B. Liedtke. Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter. PNAS, February 25, 2013 DOI: 10.1073/pnas.1300959110

Syndactyly is a name that means webbed fingers. Webbed toes is when two or more toes are fused together. In early fetal development, all human's toes and fingers are webbed together. They are separated by apoptosis that occurs by a specific enzyme. Therefore, webbed toes occur when this apoptosis either does not occur or is incomplete.

There are six different types:

Simple: adjacent fingers/toes joined by soft tissue and skin
Complex: bones of adjacent fingers or toes are fused together
Complete: the skin is joined the entire length of the digits
Incomplete: the skin is joined partially up the digit, usually to the first joint
Fenestrated: the skin is joined for most of the digit, but there is a gap in the middle of the joined skin
Polysyndactly: there is an extra digit webbed to an adjacent digit.

The cause of this is still unknown, but women smoking during pregnancy or a women's nutritional intake during early gestation can contribute. It is a side effect to over 100 different diseases, and it does occur in families.

I was curious as to what kind of development abnormalities that have occurred and this is what I found:

First of all, down syndrome is the most common chromosomal abnormality affecting 1 in 800 babies. The chances of this happening increases as the mother ages. The problem is due to an extra 21 chromosome. This leads to an over expression of those genes.

Another one that I came across is called harlequin-type ichthyosis. This is a skin disease characterized by thickening of the keratin layer in fetal human skin. What happens in the the skin contains massive, diamond-shaped scales that tend to be a reddish color. Besides that, the ears may be very poorly developed or absent entirely, same for the nose. The eyelids everted, and often bleed upon birth. the lips are fixed into a wide grimace. Arms, feet and fingers are always always deformed in that they cannot bend properly, and may be below the normal size. Because of the skin condition, it easily cracks causing an increased risk of bacterial infection. This disease is associated with a mutation in the gene for the protein ABCA12. This protein is called ATP-binding cassette transporter 12. This protein is essential for normal development of the skin. It is thought to be important for transporting lipids in cells that make up the epidermis of the skin.

Here are a few more brief genetic accidents that I came across:

Frog-like baby: In 2006, a baby was born that was neck-less. The head was almost totally sunk into the upper part of the body. Also, the eyeballs were extremely large and literally popping out of the eye-sockets. Unfortunately, the baby died within a half hour after birth.

13-inch tailed man: from a congenital defect, this man has a tail. It is located in the coccygeal end of the vertebral column, and he would not survive without it.

Cyclop Baby: In 2006, this baby was born with one eye. The medical staff believe that it was due to an experimental anti-cancer drug or from a chromosomal disorder known as cyclopia. The baby was born with a one eye in the center of her forehead, with no nose, and her brain was fused into one hemisphere. The baby was able to survive for a few days, but then, unfortunately, pasted away.

Feet facing backwards: A women in China was born with her feet facing the wrong way.

Baby with Three Arms: In 2006, a baby was born with a third arm. The arm was successfully removed, but the baby will need a long-term physical therapy to gain function in the remaining hand. That hand has no palm and flexes in either direction.

Nipple on the foot: A 22-year old women sought medical care to get a well-formed nipple surrounded by areola and hair removed from her the plantar region of her foot. Microscopic examination of the dermis showed hair follicles, eccrine glands, and sebaceous glands, alone with fat tissue on the base.

With all of these abnormalities, I am curious as to if we will ever find answers to why these happen. I am sure with how much we have discovered so far that eventually we will have out answers. However, the conditions seem so complicated that it will most likely take years and years to get to a conclusion.

(http://www.oddee.com/item_92015.aspx)

Bipolar is a highly inheritable disorder with an 80% chance of inheritance (Craddock, 1999). There has not been a single gene found that is the cause of this disorder. It is thought that several genes are involved and each raise the risk of onset. Some associated genes include: catechol-O-methyltransferase (COMT), GRK-3-BETA, monoamine oxidase (MAOA), G72/G30 gene, and the serotonin transporter gene. Most studies done need replication because they are usually family based studies. Certain families show certain genes affected, but as far as what genes are for sure involved still needs to be determined. Environmental factors also effect the onset of this disorder, which makes finding the cause much more difficult.

Cytokines are proteins that indicate internal responses to environmental stressors by promoting the inflammatory response. Cytokines have shown that they cause neuronal and glial apoptosis. Therefore, high levels of stress as a child produces high levels of cytokines and can be an important mediator in bipolar development.

During normal brain development, pruning of gray matter occurs as the brain matures. According to Gogtay's team, children with bipolar disorder have a more complicated pattern of gray matter in areas of the left hemisphere, losses in the right hemisphere, and losses in the mood regulation area in the mid-front part of the brain.

Gogtay N, Ordonez A, Herman DH, Hayashi KM, Greenstein D, Vaituzis C, Lenane M, Clasen L, Sharp W, Giedd JN, Jung D, Nugent Iii TF, Toga AW, Leibenluft E, Thompson PM, Rapoport JL. Dynamic mapping of cortical development before and after the onset of pediatric bipolar illness. J Child Psychol Psychiatry. 2007 Sep;48(9):852-62. PMID: 17714370

Craddock N, Jones I. Genetics of bipolar disorder. J Med Genet
1999;36:585-594.

Roybal, D.J., Singh, M.K., Cosgrove, V.E., Howe, M., Kelley, R., Barnea-Goraly, N., Chang, K.D. 2012. Biological evidence for a neurodevelopmental model of pediatric bipolar disorder. Isr J Psychiatry Relat Sci. (49(1): 28-43.

At the onset of heart formation, we have six aortic arches instead of three. Supposively the three that we lose were from our evolutionary history. The three arches to go away during development are arches one, two and five. In the first five stages of cardiac development the heart is a tube that has four bulges. The tube forms by the fusion of lateral plate mesoderm from two distinct cardiac fields. The heart then forms an "s" shape by factors that develops into the heart structure that we are more familiar with. One bulge is called the bulbus cordis (truncus arteriosis). This bulge continues on to form a ventricle. Another bulge called the primitive ventricle becomes the other ventricle chamber. The last two bulges are the sinus venosus and primitive atrium. The sinus venosus becomes incorporated into the wall of the right atrium, and the primitive atrium becomes the two atria. The factors that cause the "s" shape cause the heart to loop and this causes the structures that need to be posterior to move to their location, and the structures that need to be anterior move to the anterior.