passionless Droning about autism

Archive for the ‘BPA’ Category

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:

Effects of perinatal hypothyroidism on regulation of reelin and brain-derived neurotrophic factor gene expression in rat hippocampus: Role of DNA methylation and histone acetylation

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.

– pD

Hello friends –

Recently there have been a few studies that tackled the issue of apparent autism clusters in California, The spatial structure of autism in California, 1993-2001, and Geographic distribution of autism in California: A retrospective birth cohort analysis.   A nice overview and some discussion of these papers can be found at LBRB, here, and here.  One of the arguments we see made there is that the rates of autism diagnosis are, in fact, a reflection of the available services in an area, as opposed to an actual difference in the number of children with autism; essentially that an undiagnosed child with autism who lives far from a center of autism services will not get a diagnosis, but a child born relatively close to such services, will be appropriately diagnosed.  We are measuring diagnosis, as opposed to autism.  I have no doubt that there is some validity to this, but have many doubts that we can, or should, assign all of our observed increases in autism as consequences of this type of artifact. 

There have been several other studies that looked at things like mercury emissions, or airborne pollutants, or Superfund sites and autism rates at larger scales.  However, on a macro level, these types of studies have, so far, been unable to design around a feature of reality; the likelihood that things like Superfund sites or airborne pollution are situated in relative proximity to an urban center, and as such, autism diagnosis services.  In effect, the argument that these observations are diagnostic only is the same; without a controlling factor for diagnostic availability, we can not assume that other parameters are actually responsible.  And again, I have no doubt that this is a force that contributes to the findings of these studies.

But.

At the end of the day, I’m just not satisfied with a God of the Gaps explanation; what we seem to be seeing is just too goddamned important to explain away with the spongy soft and ultimately unmeasurable forces of greater awareness et all. (The Fairytale, 20##). 

Anyways, the other day pubmed alerted me to the publication of  this interesting study: 

 Body burdens of brominated flame retardants and other persistent organo-halogenated compounds and their descriptors in US girls.

BACKGROUND: Levels of brominated flame retardants are increasing in US populations, yet little data are available on body burdens of these and other persistent hormonally active agents (HAAs) in school-aged children. Exposures to such chemicals may affect a number of health outcomes related to development and reproductive function. OBJECTIVE: Determine the distribution of biomarkers of polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), and organo-chlorinated pesticides (OCPs), such as DDT/DDE, in children, and their variation by key descriptor variables. METHODS: Ethnically diverse cohorts of girls 6-8y old at baseline are being followed for growth and pubertal development in a multi-site, longitudinal study. Nearly 600 serum samples from the California and Ohio sites were analyzed for lipids, 36 PCB congeners, 11 PBDE congeners, and 9 OCPs. The biomarker distributions were examined and geometric means compared for selected analytes across categories of age, race, site, body mass index (BMI), parental education, maternal age at delivery, and breast feeding in adjusted models. RESULTS: Six PBDE congeners were detected among greater than 70% of samples, with BDE-47 having the highest concentration (median 42.2, range 4.9-855ng/g lipid). Girls in California had adjusted geometric mean (GM) PBDE levels significantly higher than girls in Ohio. Furthermore, Blacks had significantly higher adjusted GMs of all six PBDE congeners than Whites, and Hispanics had intermediate values. GMs tended to be lower among more obese girls, while other variables were not strongly associated. In contrast, GMs of the six PCB congeners most frequently detected were significantly lower among Blacks and Hispanics than Whites. PCBs and the three pesticides most frequently detected were also consistently lower among girls with high BMI, who were not breast-fed, whose mothers were younger, or whose care-givers (usually parents) were less educated. Girls in California had higher GMs than in Ohio for the pesticides and most PCB congeners, but the opposite for CB-99 and -118. CONCLUSIONS: Several of these potential HAAs were detected in nearly all of these young girls, some at relatively high levels, with variation by geographic location and other demographic factors that may reflect exposure pathways. The higher PBDE levels in California likely reflect differences in fire regulation and safety codes, with potential policy implications.

The environmental impact argument usually focuses on vaccines, or in some instances, similarly widespread environmental pollutants (i.e., mercury emissions); external forces which tend to operate more or less evenly across large geographic swaths, and also largely independent of things like culture or race.  But with this paper we can observe the counter-intuitive opposite,  chemicals that have achieved widespread distribution in society and the environment, seem to be bioaccumulating differentially according to factors such as geography, race, body type, and education levels.  The paper here mentions fire regulation as a possible factor in state by state differences, but taking things a bit further, it can quickly be seen how socio-economic factors might play a role in why we might observe different levels of chemicals.  It takes a lot of crazy chemistry to make a baby onesie not catch on fire, but at a high level, it involves dousing the material with a bunch of exotic chemicals.  Politically correct or not the facts on the ground are that the well to do white woman has baby showers where she gets a bewildering array of freshly minted, ‘extra safe’ baby clothes more often than,  say, the not so well to do Latina woman.  We have already established a connection between having older parents and a diagnosis of autism, it would seem, there is also a correlation between having older parents and your bodies burden of these molecular mimics; and again, white women tend to have babies at later stages in life than their Black or Latina counterparts; especially the ones that happen to be residing near the trendy autism diagnosis hubs (i.e., the wealthier white women).    The ability for these types of chemicals to cause a variety of difficult to predict developmental trajectories is too long, and terrifying to go into detail in this post; for purposes of this discussion, it is sufficient to understand that we have a growing body of evidence that endocrine disrupting compounds can have wide ranging effects; including epigenetic changes, changes in immune profiles, altered behaviors and neuroanatomical structures known to be abnormal in autism

I found the finding of BDE-47 particularly intriguing, considering it was used as a primer for immunological response measurement by Ashwood, who found in vitro differences in immune responses in the autism population (an exaggerated innate immune response was observed).

Of course, this study does not present sufficient evidence for us to draw conclusions about the geographic distribution of autism rates in the two California studies above; but it should give us enough to pause before we take the comforting road out and assume that our observation are the result of diagnostic artifact alone; such assumptions feel good (except for the guilt), but ultimately require that we ignore our growing knowledge of how unpredictable endocrine disruptors affect the body, and how much more we have to learn.

– pD

Hello friends –

One of my biggest problems with the Fairytale of a Static Rate of Autism is that we need to ignore the reckless environmental engineering that our species has engaged upon in the past few decades.  My concerns lay within the inherent, difficult to underestimate stupidity of our actions, wherein our perceived understanding of the impact our actions are far less pronounced than the actual impact of our actions.   For the telescopic illustration of this worldview, go back any number of years where X is greater than thirty, and see if the expectations and predictions of those times match up well with what has actually occurred.     While our achievements are great and wondrous, it is at our great peril we come to believe we understand sufficiently our actions to predict their outcomes. 

In any case, a progenitor of great concern, or indeed, impending doom, to my mind, is the increasing environmental ubiquity of a variety of industrial chemicals that have the potential to interfere with biological processes in difficult to predict ways, endocrine disruptors.   Although there are no doubt naturally occurring substances with similar properties, for purposes of this discussion, lets assume that my concern (and yours), should be with chemicals that were manufactured by man that have molecular structures so similar to naturally occurring molecules that they can interfere with low level metabolic processes in a myriad of ways that are difficult to understand without very detailed analysis.  Unfortunately, subtle effects during critical developmental time frames can propagate outward into long lasting, not so subtle effects.  Doubling down, we are largely reliant on corporations largely responsible for the next quarter share price to ascertain if subtle effects are happening or not. 

To  start the horror show, considers Bisphenol-A , a plasticizer used in pretty much everything, but especially in things like the tupperware you put in the microwave, bottles you give your baby, canned goods, or anything else you buy in the grocery that has a shelf life.  This particular mish mash of atoms tends to break down into something that is chemically very similar to estrogen, so similar, in fact, that the keys and locks of the cellular machinery of your metabolism can get confused.   It turns out, when this happens, we start seeing disturbing associations between circulating levels of BPA and a variety of conditions you’d rather not have, including heart disease and diabetes.  On top of tons of animal models of BPA exposure and metabolic dysfunction, immune changes, and we now have several human studies wherein urinary levels of these chemicals is associated with adverse outcomes.    And those are just the direct effects!

It would seem that BPA can have epigenetic effects too, wherein it can modulate which genes get expressed, and that’s a lot like getting a whole different set of genes.  For a fascinating (and terrifying) ride, I’d recommend that anyone take a look at this slide show from NOVA science now that goes over some of the effects of BPA to a prenatal environment.  I  double dog dare anyone who doesn’t think we are doomed to watch this episode. 

That was the good news. 

The uncontested facts on the ground are that, as a species, we are being exposed to BPA in ways that no previous generations of humans, or mammals, vertebrates, invertebrates, or living thing has ever been exposed to.  There is no way we are clever enough to understand the ramifications of this, and yet, we have up and distributed BPA in measurable and non trivial concentrations in every human body touched by modern convenience. 

The Scary Chemicals stories will involve research on a variety of chemicals identified as endocrine disruptors with known or suspected properties that would allow them to interact with development in ways meaningful to autism research.   BPA is one.  There are many, many others.

Oh well.

– pD


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