Comment on “Patches of Disorganization in the Neocortex of Children with Autism” by Stoner and Colleagues(1)

 

This study is being interpreted as an indication of prenatal origin of abnormalities in the brain, related to ASD.(1a)  Such an interpretation might be inappropriate and might lead to allocation of scarce research resources away from an area in which more should be done.  The study’s authors said, “Our data support a probable dysregulation… at prenatal stages.”  They seem to be uncertain about whether the problem originates prenatally, and in any case they did not appear to explain why they suspected prenatal origin.  There are good reasons why they should be uncertain, which will follow.

 

The authors found “disorganization” of brain cells, which they said could result from “migration defects.”  Regarding those defects, note that migration of brain cells is well known to continue postnatally.(2)  In addition, the U.S. Agency for Toxic Substances and Disease Registry (ATSDR) refers to “deranged neuronal cell migration” that may result from the developing nervous system’s exposure to methylmercury.  And they say that “particularly sensitive” periods of children’s neurological development to effects of developmental toxins include “the early months after birth.”(3) (emphasis added)  An EPA report to Congress stated that “neuronal migration, a process specifically affected by methylmercury…continues until five months after birth.”(3a)

 

(Considering the significance of methylmercury in this discussion, be sure to distinguish this form of mercury from the ethyl form, which some studies have found to be unrelated to autism risk.  Also note that methylmercury is usually a very major part of the total mercury in the human body.(4))

 

The authors of the Stoner study also observed “abnormal laminar cytoarchitecture” in the affected brains.  In connection with that, note that experts on neurodevelopmental toxicity point out that “lower level exposures (to methylmercury) have been associated with migration and cytoarchitectural defects.”(5)  And remember (from above) the EPA’s statement that methylmercury affects neuronal migration until five months after birth.

 

The Stoner study also found disorganization of neurons “in prefrontal and temporal cortical tissue.”  In relation to that, note that both of those specific brain sections are known either to develop extensively postnatally (in the case of the dorsolateral prefrontal cortex, where most of the disorganization was found(6)) or at least to include a section that is known to develop well into postnatal life.(7)

 

Developing fetuses and infants are both exposed to methylmercury, but in very different concentrations.  According to an EPA publication, "a wealth of information" indicates that lactational transfer of maternal mercury during the first 15 days of lactation is equal to about a third of the total transfer of mercury that takes place during gestation.(8)  A 1999 Swedish study estimated, “About 10% of the Hg (mercury) present in (a mother’s) circulating blood would be transferred to the milk every day.”(9)  It should also be noted that typical human milk has been determined to have four times the mercury concentration that is allowed in U.S. bottled water,(10) and often higher, depending on the mother’s occupational, dietary or regional exposures, and also depending on how early in the lactational period the measurement is taken. Other studies have provided additional verification of the rapid transfer of a mother’s mercury to breastfed infants.(11)

 

ASD symptoms emerge in children at ages ranging from a few months(12) to years, often occurring as regressions following apparently normal earlier development.  In parallel with that, effects of methylmercury exposure are known to the ATSDR to emerge for the first time after latent periods ranging from months to many years.(13)   Such latency of effect is apparently unusual among neurological toxins and may even be unique to methylmercury, as evidenced by the statement by the expert on neurological toxicology, D.C. Rice, who said, “Methylmercury may represent the only environmental toxicant for which there is good evidence for delayed neurotoxicity that may be manifested many years after cessation of exposure.”(13a)

 

 

There are other ways in which mercury’s effects are compatible with characteristics of ASD:  

1) A scientist and M.D. (D.T. Wigle), writing in a publication of the Oxford University Press, points out that relatively low developmental exposures to mercury cause “abnormal social behavior;(14)  those words could be describing basic traits of ASD.   

2) The ATSDR points out that major effects of methylmercury exposure include sensory dysfunction (specifically visual) and ataxia(15) (lack of muscular coordination, including poor control of eye movement);16  these effects, also, sound similar to typical traits of ASD:  clumsiness and lack of eye contact.  

3) There are many other close similarities between observed effects of mercury and traits of ASD, itemized in section 5.e at www.autism-correlations.info .

 

It should be safe to summarize that the brain’s vulnerability to effects of toxins, such as adverse effects on cell migration resulting from  methylmercury exposure, continues into the postnatal period; and methylmercury seems to fit especially well as a possible cause of the brain abnormalities found in the Stoner et al. study, since

   a) its known ability to derange neuronal migration could be at the basis of disorganization in the brain such as was observed in the study;

   b) during a period when that derangement could well be taking place, the developing organism’s exposure to that toxin is at its highest, and most infants ingest it in doses far exceeding established safe guidelines (see above),

   c) its outwardly-observable effects resemble characteristics of ASD, and

   d) perhaps uniquely among toxins to which infants are exposed, it is known to have latency of effect after exposure in a way that is very compatible with the late emergence of ASD traits following earlier normal development.

 

Acceptance of this study as evidence of prenatal origin of brain abnormalities could lead to scarce research resources’ being under-allocated to the crucial postnatal phase of neurological development.

 

Donald Meulenberg

Director

Pollution Action

27 McWhirt Loop, Ste. 111

Fredericksburg, VA  22406

 

_______________

(1) Stoner et al., Patches of Disorganization in the Neocortex of Children with Autism, New England Journal of Medicine, 2014 online at http://medicine6.com/download/8599

 

(1a) “Autism and Prenatal Development”, on Autism Speaks website March 28, 2014, at http://www.autismspeaks.org/science/science-news/autism-and-prenatal-development?utm_source=email&utm_medium=text-link&utm_campaign=sciencedigest

 

(2) Stiles et al.,The Basics of Brain Development,  Neuropsychol Rev. Dec 2010; 20(4): 327–348. Published online Nov 3, 2010  at http://www.ncbi.nlm.nih.gov/pmc/articles/pmc298900; also Tau et al., Normal Development of Brain Circuits, Neuropsychopharmacology. Jan 2010; 35(1): 147–168. Published online Sep 30, 2009.   at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055433

 

(3) U.S. ATSDR, Public Health Service, Toxicological Profile for Mercury  at www.atsdr.cdc.gov/toxprofiles/tp46.pdf,  p. 214 re “deranged” neuronal migration.  Also Section 1.6 re particularly sensitive periods of neurological development.

 

(3a)  EPA-452/R-97-009 December 1997  p. 5-29 (Section 5.6.1) at http://www.epa.gov/ttn/oarpg/t3/reports/volume7.pdf

 

(4) Mahaffey et al., Blood Organic Mercury and Dietary Mercury Intake: National Health and Nutrition Examination Survey, 1999 and 2000, top lines of Tables 2 and 4, at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1241922/pdf/ehp0112-000562.pdf

Mercury levels in studies of humans are normally not speciated, but they are mainly methylmercury;  among U.S. women with mercury concentrations in the highest 10% of those tested in the 1999-2000 NHANES survey, 92% of the mercury in their blood was methylmercury.  (Mahaffey et al., Blood Organic Mercury and Dietary Mercury Intake: National Health and Nutrition Examination Survey, 1999 and 2000, top lines ofTables 2 and 4, at www.ncbi.nlm.nih.gov/pmc/articles/PMC1241922/pdf/ehp0112-000562.pdf)

                

(5) (Adams et al., Workshop to Identify Critical Windows of Exposure for Children's Health: Neurobehavioral Work Group Summary, Environmental Health Perspectives, June 2000, at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1637822   p. 538

Also, including about effects on neuronal migration at low doses: Sass et al., Methylmercury-Induced Decrement in Neuronal Migration May Involve Cytokine-Dependent Mechanisms: A Novel Method to Assess Neuronal Movement in Vitro, Toxicological Sciences, Vol. 63, at http://toxsci.oxfordjournals.org/content/63/1/74.full

 

(6)  Gao et al., The Unique Properties of the Prefrontal Cortex and Mental Illness, InTech, 2012,  at http://neurobio.drexelmed.edu/GaoWeb/papers/Gao_etal_The_unique_properties_of_the_prefrontal_cortex_and_mental_illness_2012.pdf 

Also: Luciana, ed. by Charles A. Nelson; Monica (2001). Handbook of developmental cognitive neuroscience. Cambridge, Mass. [u.a.]: MIT Press. ISBN 0-262-14073-X

 

(7) The dentate gyrus is the section in the temporal cortex that is specifically known to continue to develop into adulthood.  Eriksson et al., Neurogenesis in the adult human hippocampus,  Nature Medicine 4, 1313 - 1317 (1998) at http://www.nature.com/nm/journal/v4/n11/full/nm1198_1313.html

 

(8)  Exploration of Perinatal Pharmacokinetic Issues, EPA/630/R-01/004, Section 4.7.4.3,  at www.epa.gov/raf/publications/pdfs/PPKFINAL.PDF  

 

(9) Vahter et al., Longitudinal Study of Methylmercury and Inorganic Mercury in Blood and Urine of Pregnant and Lactating Women, as Well as in Umbilical Cord Blood, Environmental Research, Section A 84,

186}194 (2000) at http://www.detoxmetals.com/content/FISH/FISH/Hg%20in%20pregnant%20urine%20and%20cord.pdf

 

(10)  P. 443 of U.S. ATSDR, Public Health Service, Toxicological Profile for Mercury  at http://www.atsdr.cdc.gov/toxprofiles/tp46.pdf, and Code of Federal Regulations, Title 21, Chapter 1, Subchapter B, Part 165, Subpart B, Sec. 165.110 Bottled water, fourth table in section, at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=165.110

 

(11)  Drexler et al., The mercury concentration in breast milk resulting from amalgam fillings and dietary habits,  Environ Res. 1998 May;77(2):124-9. at   http://www.ncbi.nlm.nih.gov/pubmed/9600805. This study found that concentrations of mercury in breast milk of 85 lactating women at two months after birth had declined by an average of over 70% from their levels at time of birth;   

    Also Marques et al., Hair mercury in breast-fed infants exposed to thimerosal-preserved vaccines,  Eur J Pediatr. 2007 Sep;166(9):935-41. Epub 2007 Jan 20.  at http://www.ncbi.nlm.nih.gov/pubmed/17237965.  This study of 82 mother-infant pairs found that mercury levels in mothers’ hair decreased 57% during six months of lactation;15e

 

(12) Jones et al., Attention to eyes is present but in decline in 2-6-month-old infants later diagnosed with autism : Nature:(2013) DOI:doi:10.1038/nature12715 at http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12715.html

 

(13) Section 2.6, p. 302 of U.S. ATSDR, Public Health Service, Toxicological Profile for Mercury  at http://www.atsdr.cdc.gov/toxprofiles/tp46.pdf

 

(13a) Rice DC, .Evidence for delayed neurotoxicity produced by methylmercuryNeurotoxicology. 1996 Fall-Winter;17(3-4):583-96, at at http://www.ncbi.nlm.nih.gov/pubmed/9086479www.ncbi.nlm.nih.gov/pubmed/9086479

 

(14) (D.T. Wigle, MD, PhD, MPH:  Child Health and the Environment, Oxford University Press, 2003, Ch. 5. p. 103,106, typically available through Ebsco Host at local libraries)  Note that the studies referred to by the author normally based their observations of effects of “prenatal” exposures on umbilical cord blood levels of mercury, or on both cord blood and maternal hair mercury levels; those would be good indicators of levels in breast milk, at least levels in milk that is ingested in the early, most critical period of postnatal neurological development.

 

(15) Next-to-last paragraph of Section 2.2.2.4 of U.S. ATSDR, Public Health Service, Toxicological Profile for Mercury  at http://www.atsdr.cdc.gov/toxprofiles/tp46.pdf

 

(16) From a web page of Medical News Today, at www.medicalnewstoday.com/articles/162368.php