Archive for July 2010
Hello friends –
I ran into a few abstracts, read a few papers, and tried to get my way through one really dense paper in the past few weeks that got me thinking about this post. It’s all shook up, like pasta primavera in my head, but hopefully something cogent will come out the other end. (?)
Of the metabolic conditions known to be associated with having a child with autism, hypothyroidism is one that I keep on running into by way of the pubmed alert grapevine. By way of example, we have two studies that looked for autoimmune conditions in family members which found hypothyroidism to be one of many autoimmune diseases as a risk factor for autism, including, Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism, and Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. This shouldn’t be too surprising, we know that, for example, perinatal hypothyroidism is a leading cause of mental retardation, with similar findings for the condition during pregnancy. It turns out, it appears that rates of hypothyroidism are slightly increasing, though at this time, the increases are of relatively small proportions, and as such, may be artifacts unrelated to an actual increase in classically recognized hypothyroidism. In any case, I think it is safe to say that interference with thyroid metabolism is something to be avoided at all costs when possible.
So after having read about that, this paper showed up in my inbox a while ago:
Thyroid hormones have long been known to play important roles in the development and functions of the central nervous system, however, the precise molecular mechanisms that regulate thyroid hormone-responsive gene expression are not well understood. The present study investigated the role of DNA methylaion and histone acetylation in the effects of perinatal hypothyroidism on regulation of reelin and brain-derived neurotrophic factor (BDNF) gene expression in rat hippocampus. The findings indicated that the activities of DNA methyltransferase (DNMT), methylated reelin and BDNF genes were up-regulated, whereas, the activities of histone acetylases (HAT), the levels of global acetylated histone 3 (H3) and global acetylated histone 4 (H4), and acetylated H3, acetylated H4 at reelin promoter and at BDNF gene promoter for exon II were down-regulated in the hippocampus at the developmental stage of the hypothyroid animals. These results suggest that epigenetic modification of chromatin might underlie the mechanisms of hypothyroidism-induced down-regulation of reelin and BDNF gene expression in developmental rat hippocampus
This gets interesting for autism because reelin, and bdnf levels have been found to be decreased in several studies in the autism population, with direct measurements, genetic expression, mouse knockout based models of autism , and genomic alterations all being implicated. There have been some negative genetic studies, but considering that it isn’t always the genes you have, but the genes you use, our other available evidence certainly points to BDNF and reelin involvement with some percentage of children with autism, and the association is such that a reduction in reelin or BDNF is a risk factor for developing autism. It would seem that the paper above might give some insight into the lower level details of the effects of hypothyroidism and subsequent developmental trajectories; modifications of reelin expression; through epigentic mechanisms, no less!. That’s pretty cool!
Then, I got my hands on a review paper that tries to go into detail as to the functional mechanism by which reelin deficiency could contribute to ASD, Neuroendocrine pathways altered in autism. Special role of reelin. It is a review that touches on a variety of ways that reelin contributes to neurodevelopment that have findings in the autism realm, including neuronal targeting and migration during brain formation, interactions with the serotonin and GABA systems, testosterone, and oxytocin. In short, there are plenty of ways that decreased reelin expression can impact development in ways that mirror our some of our observations in autism.
Of the many things that convince me that we are doomed, the proliferation of chemical compounds whose interactions within our bodies we scarcely understand is among them. In my readings on endocrine disruptors, one thing I found that seemed to be worrying lots of researchers was that some classes of these chemicals are capable of interfering with thyroid metabolism, and in some cases interfering with development of cells known to be associated with autism. Terrifyingly enough, since I read those papers, several others have come out, including Polybrominated Diphenylether (PBDE) Flame Retardants and Thyroid Hormone during Pregnancy and Mini-review: polybrominated diphenyl ether (PBDE) flame retardants as potential autism risk factors. At this point, it is important to point out that, as far as I know, there have not been any studies showing that non occupational exposure to PDBEs or other environmental pollutants can lead to classically defined hypothyroidism, at least none that I know of. (?) Be that as it may, I think it is realistic to assume any interference in thyroid metabolism is a bad thing, and while finding people in the outlier regions of hypo (or hyper) thyroidism gives us information on extreme environments, it would take someone with a lot of misplaced faith to assume that we can safely disturb thyroid metabolism just a little bit, and everything will come out in the wash.
I’ve had the argument made to me in the past that environmental pollutant driven increases in autism lacked biological plausible mechanisms; this argument is almost always made within a context of trying to defend the concept of a static rate of autism. While the papers I’ve linked to above do not provide conclusive proof that our changing environment is causing more children to be born with autism, they do provide increasing evidence of a pathway from pollutants to ASD, and indeed, the lack of biological plausibility becomes an increasingly flacid foundation on which to assume that our observations of an increased rate of autism are illusory. Unfortunately, in my opinion, the focus on vaccines has contributed to the mindset that a static rate of autism (or nowadays, maybe a tiny increase), must be protected at all costs, including some ideas on the application of a precautionary principle that seem outright insane to me (or at least, the exact opposite of what I would consider to be a precautionary path).
One thing is for certain, the number of child bearing women in developing countries with measurable concentrations of chemicals known to interferre with thyroid metabolism nears 100% in the industrialized nation as we eat , drink, breathe and bathe in the microscopic remnants of packaging materials, deteriorating carpet fibers, and baby clothes that are made to be fire resistant. This is an environment unambiguously different than that encountered by any other generation of infants in the history of mankind. To believe that we can modify our environment so drastically without having an impact seems incredibly naive to me, or on some days, just plain old stupid.