Thursday, June 5, 2014

Autism -- back to blaming the mother?

Two recent reports of the cause of autism reach different conclusions, though they are alike in that neither implicates genetics, at least not directly.  The first, published in the International Journal of Epidemiology ("Maternal lifestyle and environmental risk factors for autism spectrum disorders," Lyall et al.), reviews the evidence for environmental risk factors and finds that diet can influence risk, and that folic acid supplements taken around conception are associated with reduced risk.  Further,
Although many investigations have suggested no impact of maternal smoking and alcohol use on ASD [autism spectrum disorder], more rigorous exposure assessment is needed. A number of studies have demonstrated significant increases in ASD risk with estimated exposure to air pollution during the prenatal period, particularly for heavy metals and particulate matter. Little research has assessed other persistent and non-persistent organic pollutants in association with ASD specifically.
Lyall et al. call for larger epidemiological studies of maternal exposure to vitamins, fats and other nutrients, as well as pesticides and endocrine-disrupting chemicals, even though environmental epidemiological studies of autism have been done for decades.

The second paper, in  Molecular Psychiatry ("Elevated fetal steroidogenic activity in autism," Baron-Cohen et al.), reports the results of looking at hormone levels in amniotic fluid samples collected at between 15 and 16 weeks gestation from a sample taken from a registry of nearly 20,000 male infants in Denmark, born between 1993 and 1999.  The final sample was fairly small, including 128 male infants with autism and 217 controls; the 24 females in the registry who were later diagnosed with autism were excluded from the study because they were atypical for a variety of reasons.  Prevalence of autism is generally higher in males.
We find that amniotic fluid steroid hormones are elevated in those who later received diagnoses on the autism spectrum. Rather than the abnormality being restricted to a specific steroid hormone, a latent steroidogenic factor is elevated, which includes all hormones in the Δ4 pathway, as well as cortisol.
The effect on the developing brain, Baron-Cohen et al. suggest, may be epigenetic.  That is, steroids modify DNA in ways that affect gene expression without changing coding sequence.
Steroids and their receptors act as epigenetic fetal programming influences on early brain development. Through their nuclear hormone receptors, steroids can alter gene expression via direct or indirect influence on multiple epigenetic processes such as histone acetylation, DNA methylation and have transcriptional and post-transcriptional effects on noncoding mRNAs such as microRNAs. Furthermore, during early sensitive periods of brain development, there are sex differences in DNA methylation, methyl-binding proteins, chromatin modifications and microRNA expression, and these effects are mediated in part by early steroid hormone effects.
What is the source of the excess steroid?  "The fetus, the mother, the placenta or other external factors" -- that is to say, it could be anything and this study couldn't answer that question.  Indeed, it is also impossible to know, if the excess hormone really is involved, whether it's the cause of the disorder or the result.  Perhaps maternal stress is the source, the authors suggest, and perhaps, the authors note, steroids such as testosterone and cortisol are also elevated in other disorders with a skewed sex ratio.  In any case, they write, "Each of these sources require further investigation to determine how such influences might affect fetal development in autism."

Cortisol molecule

A story on the BBC website about this work quotes an autism "expert" saying that this is "an important first step" on the path to discovering what causes autism.  First step!? This is a curious way to describe things, since probably billions of dollars have been spent in the last 30 or 40 years on efforts to identify the cause of this disorder, much of it on genetic studies, with no robust results.  Given this track record, what criteria should we use to decide whether this study is worth paying any attention to?

As with many complex diseases and disorders, many genes with small effect have been identified, but none of these explains the high rates of autism now reported around the world.  It is interesting to see these two reports of possible environmental risk factors after a sea of genetic studies, though.  Decades ago autism was believed to be the result of "refrigerator mothering," but then blame swung toward genes and away from environment, and now it seems autism is epigenetic. The gene switch never could have been exactly right given the dramatic, rapid increase in prevalence of autism, and other than because genes are techy and faddish, why would one ever expect genes to be a main cause in the first place, other than as a rationale to do genetics (which we knew how to do) and a paucity of other ideas?  Or, environmental causes being difficult to replicate and confirm.

But many epidemiological studies looking for environmental causes have been done.  A 2010 paper in Current Opinion in Pediatrics reports, with respect to environmental risk factors, e.g.:
...the most powerful proof-of-concept evidence derives from studies specifically linking autism to exposures in early pregnancy – thalidomide, misoprostol, and valproic acid; maternal rubella infection; and the organophosphate insecticide, chlorpyrifos. There is no credible evidence that vaccines cause autism.
Older mothers and fathers have been associated with autism, birth order, toxic chemicals, vaccines and thimerosol, and so forth, though none reliably so.  And of those factors that have been replicated, they can't explain all cases.

Autism is a difficult trait to study.  The trait itself is hard to define, varies enormously, there are no biomarkers with which to make a definitive diagnosis, diagnostic criteria have changed over the years, and so forth.  But many traits are similarly complex -- asthma, schizophrenia, heart disease, etc. -- and similarly resistant to current methods for determining cause.  So it seems fair to assert that many attempts to determine causes of complex traits are fad-following approaches to understanding complexity with reductionist science.


Manoj Samanta said...

> Given this track record, what criteria should we use to decide
> whether this study is worth paying any attention to?

The same criteria as the ones used for learning about Kazakhstan from Borat's movies. Wiki says the first author is Borat's cousin -

Anne Buchanan said...

Now that is the most important thing this whole exercise has taught me. Thank you, Manoj!

bluets said...

I would bet external factors play a big role, from 2 sources.
(1) Air pollution carries not just chemicals (that induces physiological stress) but also microbes that could impart yet another form of physiological stress (and maternal air pollution exposure correlates with higher autism numbers);

(2) general maternal gut flora could play a major role (gut flora also can have epigenetic effects), but gut flora can be tweaked by diet and by environment (particularly drinking water - American sewage treatment is deplorably outdated)...

so we don't need to blame mom directly. we ought to be blaming society at large for our destruction of our environment.

Thiago Carvalho said...

Some good (and brief) thoughts on the state of autism spectrum disorder genetics from Martin Raff (link is open access):

Anne Buchanan said...

Thanks. Yes, it's complicated.