A Tall Tale - and about to Topple
According to Waly et al
"The ethylmercury-containing preservative thimerosal inhibited both IGF-1- and dopamine-stimulated methylation with an IC50 of 1 nM and eliminated MS activity. Our findings outline a novel growth factor signaling pathway that regulates MS activity and thereby modulates methylation reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury, aluminum and thimerosal suggests that it may be an important target of neurodevelopmental toxins."Note that in the body of their article they clarify that:
“our findings suggest that impaired methylation, particularly impaired DNA methylation in response to growth factors, may be an important molecular mechanism leading to developmental disorders”
It’s the growth factor angle that they find compelling.
Geier, Pere et Fils postulated a block in the conversion of DHEA to DHEA-S.
Dr Geier's remarks on Radio Liberty (June 23 2006) were quite explanatory:
“it turns out that these kids almost all have low glutathione, which is the substance the body makes to help get rid of heavy metal. And they’ve been exposed to mercury, and when they have that condition, when they start making their androgens, their testosterone, they get to a point, a branch point, where they’re supposed to make most of their, it’s called DHEA into DHEA-S, but they can’t make DHEA-S because they need glutathione to do that step, so they make it almost all into testosterone.”
They also said on the autismfair media video (Part 2) that:
[Their theoretical model described in Medical Hypotheses] "predicted that these children would have a low DHEA-S.
It predicts that autistics would have a high rate of precocious puberty. In fact we’re beginning to think that it’s close to 100% if you look carefully. "
So far, this has been plain sailing for the autism as mercury poisoning hypotheses of biological plausibility, but as they say, the truth will out, eventually.
Here is the abstract from IMFAR 2006, of a study from the National Institutes of Health.
"Elevated Levels of Growth-Related Hormones in Autism andAutism Spectrum Disorder James Louis Mills, Mary L. Hediger, Cynthia A. Molloy,George P. Chrousos, Patricia Manning-Courtney, Kai F. Yu, Mark Brasington, Lucinda J. England, NICHD, National Institutes of Health
Background: Autistic children are known to have larger head circumferences; whether they are also taller and heavier is less clear. Little is known about growth-related hormone levels in autistic children.Objectives: To determine whether autistic children were taller, heavier, and have higher levels of growth-related hormones than control children.Methods: Boys with autism spectrum disorder (ASD) or autism (n= 71) and age-matched controls(n= 59) had height, weight and head circumference measurements. Blood samples were assayed for IGF-1, IGF-2, IGFBP3, growth hormone binding protein (GHBP) and for DHEA and DHEAS.
Results: The autism/ASD cases had significantly (p=.03) greater mean head circumferences (z score1.24, SD 1.35) than controls (z-score 0.78, SD 0.93). Cases also had significantly (p=.01)greater weights (z-score 0.91, SD 1.13) than controls (z-score 0.41, SD 1.11). Heights did not differ significantly between groups (p=.65); however, cases had significantly (p=.003) higher bodymass indices (z-score 0.85, SD 1.19) than controls (z-score 0.24, SD 1.17). The case groups levels of IGF-1, IGF-2, IGFBP3 and GHBP were all significantly higher (p<.0001), and cases were more likely than controls to have detectable levels of DHEAS (41% vs. 24%, p=.03).
Conclusion: Boys with autism/ASD had significantly higher levels of many growth-related hormones. These findings could help explain the significantly higher head circumferences, weights and BMIs we found. Future studies should examine the potential role of growth-related hormones in the pathophysiology of autism.
Funding: Intramural research program, NICHD, NIH."
Unlike Waly et al’s kitchen sink hypothesis (i.e. in vitro) that IGF-1 is severely compromised in autistics by virtue of exposure to mercury and other things, it appears that in the real world, autistics seem to be bathing in an abundance of the stuff as evidenced by their head circumference and stature, not a runty dwarf in sight.
Dr Mills was kind enough to send me a copy of their presentation; the paper is in preparation. Here are some of their findings re DHEA and DHEA-S.
"More autism/ASD subjects (29/71) than control subjects (14/59) had measurable DHEAS levels, p=0.03
DHEA levels were detected in nearly all subjects. Levels in the autism/ASD group (66.8 ng/dL) did not differ significantly from levels in the control group (61.0 ng/dL), p=0.73
Levels of adrenal hormones were not impressively different between the autism/ASD and control groups. This suggests that earlier sexual maturation is not the explanation for our results" (emphasis mine)
Given that these results are based on 71 ASD boys between the ages of 4 and 8, with an aged matched control of 59 there should be a horde of precociously pubescent autistics. In fact, the results would suggest that Geier and Geier, according to their theory of biochemical pathway blockage (due to glutathione depletion) would be better off looking for hyperandrogenicity among the non-autistic population. It should be twice as likely in the non autistic population, given that they aren't producing DHEA-S at the same rate, thereby converting all their androgen steroid precursors into testosterone. That however, would presuppose that the Geier view of the biochemical basis of androgen synthesis is correct. That may be a supposition too far. Mills et al in their presentation have this to say about DHEA-S:
"DHEAS levels are often undetectable between infancy and the start of adrenarche (puberty)
Thus, DHEAS may be useful as a marker for the early stages of pubertal development"
It seems to me that Geier & Geier are implying that low or no DHEA-S has rather sinister connotations - indicative of hyperandrogenicity. Whereas the innocent explanation is that these children are simply pre-pubescent and what's wrong with that? Everybody is, at some point on their way to adulthood.
The conclusion to be drawn from the Geier's unique view of endocrinology is that biochemistry is fertile ground for running a scam, simply because it's so complicated conceptually and has such complicated language that it's fairly easy to sound as if you know what you're talking about. It also has the advantage of all frontiers in that, since there is a lot of conjecture about how a lot of things work, it's rather harder to prove that it is a scam. There are, however, the odd road signs.
General biochemical mechanisms such as the role of glutathione do not lend themselves readily to single outcome issues. If androgen synthesis goes haywire because of glutathione depletion, then other things should go equally haywire, like why is it that autistics do not have frequent episodes of haemolytic anemia, a feature of glutathione depletion. Ditto, for IGF-1 inhibition. It’s one of the growth hormones so one would expect sequelae beyond neurodevelopmental retardation – stunted growth for instance. But there isn’t, as Mills et al point out. It should be emphasised that Waly et al are not running a scam. Mills et al made it clear that their quantification of growth hormones in autistics was the first ever conducted. Hence, it could be concluded that mercury is unlikely to be a factor in the aetiology of autism. No matter how many environmental nasties there are out there capable of blocking methylation pathways through IGF-1, this growth hormone is curiously unaffected in real autistics in real life.
The glutathione problem remains, but looks to have been overstated. Firstly the real problem is not dangerously lowered levels, obviously (no haemolytic anaemia), but the ratio of reduced glutathione to oxidised glutathione. In autistics this seems to indicate oxidative stress. The reasons for that, however, do not have to have anything to do with heavy metal toxicity. Stress will do it and we know from cortisol studies that autistics tend to live in excessively stressful environments. It seems also that the significance of Jill James findings is in some doubt. The IOM told Bradstreet that both his and James p values were not mathematically possible and should be recalculated. They might still reach significant values, just not as startling as p<.001. Notably, Geier & Geier used the uncorrected values in their presentation at the Autism One 2006 Conference.
Disclaimer: I actually have credentials in Bichemistry. However, it’s so rusty, it’s corroded. I leave this issue to other and more up to snuff biochemists to probe further.