Wednesday, September 26, 2012

Are your children always on your mind? They may be IN your mind

Hmm. Do I have any cells in there?
On Mother's Day this year, we told you why, if you have biological children, those children are literally a part of you for life thanks to a phenomenon called microchimerism. When a woman is pregnant, some of the fetal cells slip past the barrier between mother and fetus and take up residence in the mother. What researchers hadn't turned up in humans before now was that some of those cells can end up in the mother's brain. Once there, according to a study published today in PLoS ONE, they can stick around for decades and, the researchers suggest, might have a link to Alzheimer's disease. Note that is a big "might."

The easiest way to tell if a fetal cell's made it into a maternal tissue is to look for cells carrying a Y chromosome or a Y gene sequence (not all fetuses developing as male carry a Y chromosome, but that's a post for another time). As you probably know, most women don't carry a Y chromosome in their own cells (but some do; another post for another time). In this study, researchers examined postmortem brain tissue from 26 women who had no detectable neurological disease and 33 women who'd had Alzheimer's disease; the women's ages at death ranged from 32 to 101. They found that almost two thirds (37) of all of the women tested had evidence of the Y chromosome gene in their brains, in several brain regions. The blue spots in the image below highlight cells carrying these "male" genes a woman's brain tissue.

Photo Credit: Chan WFN, Gurnot C, Montine TJ, Sonnen JA, Guthrie KA, et al. (2012)
Male Microchimerism in the Human Female Brain. 
PLoS ONE 7(9): e45592. doi:10.1371/journal.pone.0045592

The researchers also looked at whether or not these blue spots were more (or less) frequent in the brains of women with Alzheimer's disease compared to women who'd had no known neurological disease. Although their results hint at a possible association, it wasn't significant. Because the pregnancy history of the women was largely unknown, there's no real evidence here that pregnancy can heighten your Alzheimer's risk or that being pregnant with or bearing a boy can help or hinder. As I discuss below, you can end up with some Y chromosome-bearing cells without ever having been pregnant.

Also, age could be an issue. Based on the reported age ranges of the group, the women without Alzheimer's were on average younger at death (70 vs 79), with the youngest being only 32 (the youngest in Alzheimer's group at death was 54). No one knows if the women who died at younger ages might later have developed Alzheimer's. 

Indeed, most of this group--Alzheimer's or not--had these Y-chromosome cells present in the brain. The authors say that 18 of the 26 samples from women who'd had no neurologic disease were positive for these "male" cells--that's 69%--while 19 of the 33 who had Alzheimer's were. That's 58%. In other words, a greater percentage of women who'd not had Alzheimer's in life were carrying around these male-positive cells compared to women who had developed Alzheimer's. The age difference might also matter here, though, if these microchimeric cells tend to fade with age, although the researchers did get a positive result in the brain of a woman who was 94 when she died.

Thus, the simple fact of having male-positive cells (ETA: or not enough of them) in the brain doesn't mean You Will Develop Alzheimer's, which is itself a complex disease with many contributing factors. The researchers looked at this potential link because some studies have found a higher rate of Alzheimer's among women who've been pregnant compared to women who have not and an earlier onset among women with a history of pregnancy. The possible reasons for this association range from false correlation to any number of effects of pregnancy, childbearing, or parenting.

Nothing about this study means that migration of fetal cells to the brain is limited to cells carrying Y chromosomes. It's just that in someone who is XX, it's pretty straightforward to find a Y chromosome gene. Finding a "foreign" X-linked gene in an XX person would be much more difficult. Also, a woman doesn't have to have borne a pregnancy to term to have acquired these fetal cells. As the authors observe, even women without sons can have these Y-associated cells from pregnancies that were aborted or ended prematurely or from a "vanished" male twin in a pregnancy that did go to term. 

In fact, a woman doesn't even have to have ever been pregnant at all to be carrying some cells with Y chromosomes. Another way you can end up with Y chromosome cells in an XX chromosome body is--get this--from having an older male sibling who, presumably, left a few cellular gifts behind in the womb where you later developed. As the oldest sibling, I can only assume I could have done the same for the siblings who followed me. So, if you've got an older sibling and have been pregnant before--could you be a double microchimera? 

But wait. You could even be a triple microchimera! This microchimerism thing can be a two-way street. If you're a woman with biological children, those children already carry around part of you in the nuclear DNA you contributed and all of the mitochondria (including mitochondrial DNA) in all of their cells. Yes, they get more DNA from you than from the father. But they might also be toting complete versions of your cells, just as you have cells from them, although fetus-->mother transfer is more common than mother-->fetus transfer. The same could have happened between you and your biological mother. If so, a woman could potentially be living with cells from her mother, older sibling, and her children mixed in with her own boring old self cells.

The triple microchimera thing might be a tad dizzying, particularly the idea that you could be walking around with your mother's and sibling's cells hanging out in You, a whole new level of family relationships. But if you're a biological mother, perhaps you might find it comforting to know that a cellular part of you may accompany your child everywhere, even as your child is always on your mind--and possibly in it, too.

3 comments:

  1. I think we should temper this result by looking closely at the methods. The experimental design here was not rigorous and they only verified one sample using something other than real-time PCR. This is a qRT No-No.

    The pregnancy status of MOST of the samples was not known. Explaining away the fact that one of the women that never had a male child was positive by PCR for male DNA by saying that she was probably a double microchimera or had an aborted male fetus is a bit of a stretch. Is it possible? Sure, but it's not verifiable so why even propose the hypothesis?

    Here are my thoughts:
    http://www.labspaces.net/blog/1601/Got_fetal_DNA_on_the_brain_

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    1. Thanks for your comment. Our focus in this piece was mitigating any interpretations about Alzheimer's and expanding on the idea of microchimerism for our general readership audience. Thank you for offering a methods critique, as well. I believe that you can add your critique in the comments related to the paper over at PLoS ONE ... perhaps the authors will address them.

      I didn't get the impression that the authors were trying to "explain" away much, but why is it a stretch to say that a woman who's had an aborted male fetus could be a microchimera? Also, as fetal cells have also been identified in CSF, I think it's feasible that they're present in the brain, as well.

      They do cite several related references for the possible ways this Y-related microchimerism can arise. Titles and links for those refs are listed below for any readers interested in checking those out:

      Cells from a vanished twin as a source of microchimerism 40 years later
      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023624/

      Male microchimerism in women with systemic sclerosis and healthy women who have never given birth to a son
      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1755528/

      Male microchimerism in women without sons: quantitative assessment and correlation with pregnancy history
      http://www.ncbi.nlm.nih.gov/pubmed/16084184

      Significant fetal-maternal hemorrhage after termination of pregnancy: implications for development of fetal cell microchimerism
      http://www.ncbi.nlm.nih.gov/pubmed/11262475

      Microchimerism after induced or spontaneous abortion (this one just reports not finding them in the circulation shortly after)
      http://www.ncbi.nlm.nih.gov/pubmed/18757657

      Maternal and sibling microchimerism in twins and triplets discordant for neonatal lupus syndrome-congenital heart block
      http://www.ncbi.nlm.nih.gov/pubmed/15536065

      A new case of human chimerism detected after pregnancy: 46,XY karyotype in the lymphocytes of a woman. (an old paper)
      http://www.ncbi.nlm.nih.gov/pubmed/3414310

      Blood transfusion: Survival of donor leukocyte subpopulations in immunocompetent transfusion recipients: frequent long-term microchimerism in severe trauma patients
      http://www.ncbi.nlm.nih.gov/pubmed/10216112

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  2. Sorry, I meant to switch those. I thought the double microchimera hypothesis was a stretch, the aborted fetus is much more plausible but still unverifiable. My feeling is that because the conclusions are mostly based on qRT data that wasn't supported by a second test that it's really hard to tell which data are accurate or to draw any conclusions at all beyond their one case where they have very high male DNA load and an in situ hybridization to back it up. Thanks for the links.

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