passionless Droning about autism

Archive for the ‘The Fairytale’ 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 –

I ran across this one on accident the other day (why wasn’t it in one of my pubmed alerts?):

Gestational Age at Delivery and Special Educational Need: Retrospective Cohort Study of 407,503 Schoolchildren

Background

Previous studies have demonstrated an association between preterm delivery and increased risk of special educational need (SEN). The aim of our study was to examine the risk of SEN across the full range of gestation.

Methods and Findings

We conducted a population-based, retrospective study by linking school census data on the 407,503 eligible school-aged children resident in 19 Scottish Local Authority areas (total population 3.8 million) to their routine birth data. SEN was recorded in 17,784 (4.9%) children; 1,565 (8.4%) of those born preterm and 16,219 (4.7%) of those born at term. The risk of SEN increased across the whole range of gestation from 40 to 24 wk: 37–39 wk adjusted odds ratio (OR) 1.16, 95% confidence interval (CI) 1.12–1.20; 33–36 wk adjusted OR 1.53, 95% CI 1.43–1.63; 28–32 wk adjusted OR 2.66, 95% CI 2.38–2.97; 24–27 wk adjusted OR 6.92, 95% CI 5.58–8.58. There was no interaction between elective versus spontaneous delivery. Overall, gestation at delivery accounted for 10% of the adjusted population attributable fraction of SEN. Because of their high frequency, early term deliveries (37–39 wk) accounted for 5.5% of cases of SEN compared with preterm deliveries (<37 wk), which accounted for only 3.6% of cases.

Conclusions

Gestation at delivery had a strong, dose-dependent relationship with SEN that was apparent across the whole range of gestation. Because early term delivery is more common than preterm delivery, the former accounts for a higher percentage of SEN cases. Our findings have important implications for clinical practice in relation to the timing of elective delivery

[Full paper from link.  Emphasis is mine]

Essentially the authors evaluated gestational lengths with a fine tooth comb to discern if ‘early’, though not technically ‘pre-term’ delivery was associated with a ‘special education need’ (SEN), which in this case embodies a range of developmental problems including dyslexia, autism, or even physical problems like deafness or vision problems.

What the authors found was that there were subtle, but real effects in the likelyhood of having a special education need for non full term births that was dose dependent, but even included children that would not necessarily be considered early by existing standards.

Our study demonstrated a strong trend of decreasing risk of SEN with advancing gestational age at birth. The key finding of the present analysis is that this trend continued across gestational ages classified as term. Although the risk of SEN was highest among infants who were delivered preterm (<37 wk gestation), these accounted for only 5.1% of deliveries. Therefore, only a relatively small proportion of SEN (3.5%) could be attributed to preterm delivery. By contrast, 39.6% of infants were delivered between 37 and 39 wk gestation. Therefore, whilst these early term infants had only a moderately increased risk, 5.3% of SEN cases could be attributed to early term delivery.

The authors claim that the finding of effects at early, but not pre-term gestational  lengths is one that is largely  missing from existing studies, which have not taken these date ranges into consideration, or the ones  that did, were not studying for cognitive problems, and indeed, excluded children with these criteria.  Curiously, they also report an increase in SEN in children who had extra gestational periods, i.e., > 41 weeks in some studies.

The authors make absolutely no speculation as to what might be driving increased special education needs as the result of premature or early birth.

Looking at their results, one of the most striking things is that the impact did not alter if elective (i.e. C-Section) versus non-elective births were used as a variable. But this has deep ramifications for the autism storyline, which holds that if there are environmental factors that can contribute to autism, they are prenatal, and indeed, are often thought to involve insults very early in the prenatal period.  In this case, we know that a genetic or environmental force isn’t contributing to the early birth, because it didn’t matter if the birth was spontaneous or not.  The only area for an effect is postnatal. That is a big, big difference in the narrative.

Is this a matter of some just in time epigenetic programming happening in the womb that doesn’t get a chance to finish up in early births?  Alternatively it could be that early birth allows for environmental exposures that the infant is not quite prepared to deal with.  Or it could be both, or neither, or an illusory finding, but if these findings can be replicated, it raises a lot of questions about the sacred line between prenatal and postnatal environmental influences.

Unfortunately, the raw data for this project  doesn’t seem to be available online; it might be really nice to see if there were patterns to be observed had particular salience to our population of interest.

–          pD

Hello friends –

So this is a really cool paper by some folks that have a series of interesting stuff:  Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain.  Here is the abstract:

Autism is currently considered a multigene disorder with epigenetic influences. To investigate the contribution of DNA methylation to autism spectrum disorders, we have recently completed large-scale methylation profiling by CpG island microarray analysis of lymphoblastoid cell lines derived from monozygotic twins discordant for diagnosis of autism and their nonautistic siblings. Methylation profiling revealed many candidate genes differentially methylated between discordant MZ twins as well as between both twins and nonautistic siblings. Bioinformatics analysis of the differentially methylated genes demonstrated enrichment for high-level functions including gene transcription, nervous system development, cell death/survival, and other biological processes implicated in autism. The methylation status of 2 of these candidate genes, BCL-2 and retinoic acid-related orphan receptor alpha (RORA), was further confirmed by bisulfite sequencing and methylation-specific PCR, respectively. Immunohistochemical analyses of tissue arrays containing slices of the cerebellum and frontal cortex of autistic and age- and sex-matched control subjects revealed decreased expression of RORA and BCL-2 proteins in the autistic brain. Our data thus confirm the role of epigenetic regulation of gene expression via differential DNA methylation in idiopathic autism, and furthermore link molecular changes in a peripheral cell model with brain pathobiology in autism.

 [As always, any emphasis is my own.]

This group has published a couple of papers that utilized similar study groups, methodologies, and means to display their findings, all of which I would recommend to anyone interested in learning; specifically, Gene expression profiling of lymphoblastoid cell lines from monozygotic twins discordant in severity of autism reveals differential regulation of neurologically relevant genes [full paper available!], Gene expression profiling differentiates autism case-controls and phenotypic variants of autism spectrum disorders: evidence for circadian rhythm dysfunction in severe autism [full version available!], and Gene expression profiling of lymphoblasts from autistic and nonaffected sib pairs: altered pathways in neuronal development and steroid biosynthesis [full paper available!]. 
There are a couple of things I really like about their methodology and presentation style. 

1) Several studies, including the most recent, included twins with discordant autism severity as study participants as a way to gain insight into the impact of genetic expression, as opposed to genetic structure on autistic behaviors.  The highly cited heritability of autism in twins is used as evidence that the condition is predominantly mediated through genetics, and while no doubt genetic structure is important, by using genetic clones with different manifestations of autism severity, the authors are able to ascertain information about which genes are being affected in twins. 

2) The two stage nature of the study design allows for both large scale analysis of a great number of genes being expressed differentially by genome wide scan, the results of which can be used for highly targeted confirmation by tissue analysis.  Further, the use of cells available in the periphery, lymphobastoid cell lines (LLCs) as measurement points for genetic expression, allows for well thought out investigations of a very rare resource, post morten brain tissue from autistics.  In this instance, different methylation profiles identified from LLCs from blood samples gave the researchers a starting point for what to look for in the brain tissue. 

3) This paper ties together both genetic expression and epigenetics; i.e., not only that genes are being used differently, but it forwards our understandings of the means by which this is happening.  Earlier studies by this group have found differences in genetic expression previously, but hadn’t elucidated on the specific mechanisms of action, in this case, over methylation, and consequent silencing of genetic protein production. 

4) This is the first group of papers I’ve seen that have been using a bioinformatics approach to understanding the pathways affected by their findings; there may be other papers out there in the autism realm, (and almost certainly in others), that have been performing this type of analysis, but I haven’t run into them.  Several of their papers, including the circadian rhythm paper, provide illustrations of associations to biological conditions and pathologies associated with affected networks.  Here is an example from the latest paper.  (Sarcastic apologies for those running at 800 / 600)
 This type of illustration is the death knell for the argument that autism is a condition to be handled by psychologists; there are a couple of similar ones in the paper. 

Considering those points, here are some juicy parts from the paper itself.  From the introduction:

In this study, we use global methylation profiling of discordantly diagnosed monozygotic twins and their nonautistic siblings on CpG island arrays to test the hypothesis that differential gene expression in idiopathic autism is, at least in part, the result of aberrant methylation. Our study reveals distinct methylation differences in multiple genes between the discordant MZ twins as well as common epigenetic differences distinguishing the twins (the undiagnosed twin exhibiting milder autistic traits that are below the threshold for diagnosis) from nonautistic sibling controls.

There are essentially three groups, twins with different autism severity, and non autistic siblings.  One thing that I’m not cerrtain of here is whether or not there were methylation differences found between the twins and their non autistic siblings or not; the text above is a little unclear; i.e., as there are different mechanisms by which genetic expression can be modified besides methylation, this may mean that while there were expression differences found between autism and controls, those differences were not found to be attributed to differential methylation levels.  (?)

From the results:

Network analysis was then performed to examine the relationship between this set of genes and biological processes. As shown in Fig. 1B, many of the associated processes within the network, including synaptic regulation, fetal development, morphogenesis, apoptosis, inflammation, digestion, steroid biosynthesis, and mental deficiency, have been associated with autism. Two genes from this network, BCL-2 and RORA, were selected for further study because of their respective roles in apoptosis and morphogenesis/inflammation. Interestingly, BCL-2 protein has been previously demonstrated to be reduced in the cerebellum and frontal cortex of autistic subjects relative to control subjects (31, 32), but RORA, a nuclear steroid hormone receptor and transcriptional activator that is involved in Purkinje cell differentiation (33) and cerebellar development (34), has never before been implicated in autism. In addition, RORA, a regulator of circadian rhythm (35), is also neuroprotective against inflammation and oxidative stress (36), both of which are increased in autism (37, 38).

Several of the tables are pretty cumbersome to paste in, but do provide more detailed functional level impacts of some of the functions of the differentially methylated genes identified.  Even with the text above, however, we can see a lot of sweet spots being touched on, including several that were identified in previous studies by this group of researchers.  It also illustrates some of the very powerful techniques in use; a broad array of genes were scanned for differential expression, some with different expression and significant roles in processes known to be abnormal in the autism population are identified, and used for further, more pinpointed analysis. 

As noted, Fatemi found reduced BCL-2 in post mortem brain samples in two studies; one of the roles played by BCL-2 is apoptosis, or programmed cell death.  By way of example, here is a study that shows that knockout (or in this case, knockup) mice that overexpress BCL-2 have more Purkinje cells than their non modified counterparts, which states, in part:

Because bcl-2 overexpression has been shown to rescue other neurons from programmed cell death, the increase in Purkinje cell numbers in overexpressing bcl-2 transgenics suggests that Purkinje cells undergo a period of cell death during normal development.

Considering that reductions in Purkinje cells is among the most commonly found brain difference in autism, a reduction in BCL-2 seems appropriate.  The fact that it in this case it was methylation levels leading to a reduction in BCL-2 might also be of interest in regards to the Fairytale Of The Static Rate of Autism; here we have evidence that mechanisms other than genetic structure are leading to decreases in a protein known to protect Purkinje cells from apoptosis.  

I don’t know anything about RORA, but its list of functions make a lot of sense when we consider other findings; a relative dearth of a protein known to protect against neuroinflammation and oxidative stress and a regulatory role in the sleep cycle.

The authors also noticed a dose dependent relationship between expression levels, which in this case represented a silencing of genes and autism severity. 

Quantitative RT-PCR was used to confirm decreased expression of BCL-2 and RORA in autistic samples and to evaluate the effect of a global methylation inhibitor, 5-Aza-2-deoxycytidine, on gene expression. For both BCL-2 and RORA, gene expression was significantly higher (P_0.05) in the unaffected control than autistic co-twins (Fig. 4A). Generally, the diagnosed autistic co-twin (_A) had the lowest level of expression of BCL-2 and RORA, while the milder undiagnosed co-twin (_M) exhibited transcript levels between that observed for unaffected sibling controls and autistic co-twins. This suggests a quantitative relationship between phenotype and gene expression of these 2 genes, although additional studies are required to confirm this observation

Again, this makes plenty of sense if we believe that things like a neuroinflammation, oxidative stress have parts to play in the behavioral manifestation of autism; in this case, get more methylation, and hence, less RORA and BCL-2, which, in turns, makes you more susceptible to neuroinflammation, oxidative stress, and Purkinje cell development abnormalities. 

If we take the predisposition towards problems with inflammation for a closer look, we can find that several other papers, including Grigorenko, Enzo, and Ashwood have all found that a propensity for inflammation, or a propensity towards abnormal regulation of inflammation have correlations with autism severity.  Though potentially inconvenient, this would seem to lend additional evidence for a causal role of immune based pathology in autism, as opposed to autism causing immune abnormalities. 

The discussions section has a lot of good text that is largely a touch up on what we already have here.  Here are some good quotes:

In particular, functional and pathway analyses of the differentially  methylated/expressed genes showed enrichment of genes involved in inflammation and apoptosis, cellulardifferentiation, brain morphogenesis, growth rate, cytokine production, myelination, synaptic regulation, learning, and steroid biosynthesis, all of which have been shown to be altered in ASDs. The candidate genes were prioritized for further analyses by identifying the overlap between the differentially methylated genes and those that had been shown to be differentially expressed in the same set of samples in previous gene expression analyses (18). Pathway analyses of this filtered set of genes thus focused our attention on 2 genes, BCL-2 and RORA, as potential candidate genes for ASDs whose expression may be dysregulated byaberrant methylation.  As shown in Figs. 3 and 4, respectively, RORA was confirmed to be inversely differentially methylated and expressed in LCLs from autistic vs. nonautistic siblings,with expression dependent on methylation, as demonstrated by the absence of methylation in the presence of 5-Aza-2-deoxycytidine. Notably, we also show by immunohistochemical staining of cerebellar and frontal cortex regions of autistic vs. normal brain (Figs. 5, 8), that RORA protein is noticeably reduced in the majority ofthe autistic samples relative to age- and sex-matched controls. This reduction is also specifically demonstrated in Purkinje cells, which are dependent on RORA for both survival and differentiation (Fig. 7). These findings thus link molecular changes identified in a peripheral cell model of ASDs to actual pathological changes in the autistic brain, suggesting that LCLs is an appropriate surrogate for studies on autism.

Finally, this paper generated a lot of press, in part (I think), because somewhere, someone (the authors?), apparently made note of the fact that this type of feature, hypermethylation, is potentially treatable, raising the possibility of palliative avenues.  (Or was this just a function of the fact that it was a finding that wasn’t truly genetic, and thus, ‘fixable’?)  While technically true, I am of the opinion that this is a long ways off; the authors found large numbers of differentially methylated genes; some were also hypomethylated.  The drugs that we know are capable of epigenomic modifications right now, some are used in advanced cancer patients, for example, are not discriminatory in their actions.  What we really would need would be targeted unmethylators that we could use to attach to RORA and BCL-2 genes and specifically free them up to produce more protein.  The same week that this paper came out, another paper was published, entitled Epigenetic approaches to psychiatric disorders which speaks towards this complexity. 

–      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

Hello friends –

This post really ought to be Chapter 1, but since I wrote the other post first, and sort of liked the title, so  we’ll just pretend; these posts are all about make believe in any case, right?

There is only one valid reason not to vigorously pursue environmental causes of autism; you need to believe that our observation of an increased rate of autism, one hundred percent of it, is an artifact of the four horsemen of the imaginary increase:

  • Diagnostic Substitution
  • Greater Awareness
  • Increased Accessibility to Diagnosis
  • Widening of Diagnostic Criteria

Lets start off with a couple of honest admissions and the reason they don’t make a whit of difference if our goal is to expose the notion of a static rate of autism as a fairytale, and a dangerous one at that. 

  • I have read very few papers regarding prevalence fully.  In fact, I can’t think of the title of a single one.   In the context of a precautionary principle, however, the methods and discussion for this type of study don’t really matter much;  because the brush strokes used to craft the results are so necessarily broad and imprecise that they are admitted as meaningless even by people who believe in the fairytale.  Think about it.   The only way we have a static rate of autism is if all of our previous studies utilized methods of such poor quality that they missed ##-## per 100,000 cases of autism, where you get to replace ##-## with any set of numbers lower than 100 as you move backwards in time.  The conclusions in our previous prevalence studies are so discordant over time that the flaws in their methodology are the super strings of the fairytale; responsible for all of our observations of increased autism rates while having  natural physical properties that render them impossible to elucidate on completely.  Given that even the proponents of the fairytale don’t give the methods of previous studies any currency, why should anyone? 

 

  • I cannot provide meaningful estimates on what percentage of the observed increase in rates is real versus artifact.  Again, however, in the prism of a precautionary principle, it doesn’t matter, because any amount of real increase is alarming, and the only possible unalarming possibility is a zero percent increase.  Here is a little thought exercise to illustrate this; imagine you are on a debate team and the topic is; “Autism rates have risen by X percent, health crisis or not?” and your team has drawn the ‘not a crisis’ side.  Insert any number greater than zero for X, and then try to construct debate points to make this argument to a crowd of skeptics.  This argument is implied whenever the fairytale is invoked, sometimes with the assertion that any real increase is “minor”, but one surefire way to get a storyteller to dissolve from a discussion is to try to get a value more concrete than “minor”  for X.   Autism is a disability, and while there are arguments to be made that it is also a ‘difference’, it isn’t a difference like having red hair or being left handed anymore than dyslexia is a different way of reading; any true increase has broad implications for us all. 

 

  • I have no doubt that the four factors listed above are, indeed, responsible to one degree or another towards what we are observing in autism rates.   Unfortunately, unless we are able to explain our ever rising rates of autism completely with these explanations, we still must contend with ramifications of a true increase.  

Even with the above caveats, a compelling case can be made that what we are observing is comprised of an actual increase in behaviors consistent with an autism diagnosis,  and the argument that autism rates are static is long on faith and very low on the lifeblood of science; reliable data. 

– pD


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