A short sentence in the abstract to a paper by Kiani and colleagues* caught my attention recently. The paper reported on the distribution of autism spectrum and other conditions in the UK according to defined designations of geographical location. In other words, whether there were any differences in reported rates according to whether people were living in a rural or an urban area. The authors suggested that among their sample (N=2713), autism spectrum disorders in particular, were more common in people living in rural areas.
I was interested in this work for several reasons. Quite a few years ago an undergraduate psychology student - 'Big bad BB' (you know who you are) - came and did some work with us involving pin-mapping where people with autism and related conditions resided on a large map of the UK. I need to track down the results which were published as conference proceedings to check but I faintly remember some interesting 'trends' emerging from this data not entirely dissimilar from the current paper.
Of course there could be lots of reasons to account for the reported results. Socio-economic status, where people work, or just a wish for a bit of quiet and tranquillity are a few factors. Those of you who regularly read this and my other blog might also pick up a bit of interest in the 'chemical world' around us, and in particular the various descriptions of exposure patterns and relative risk of lots of things. Suffice to say that when I think about rural areas and countryside, apart from rolling hills and cows and sheep chewing the cud, I unfortunately also tend to think 'pesticides'.
I'm not on this occasion going to get too alarmist based on the findings of the current paper. Trawling back through the research archives, the data is fairly mixed when it comes to asking the question 'where do you live' with regards to autism. This paper based on Taiwanese data suggested that residing in rural parts was actually less likely to get you an autism diagnosis than being an urban dweller but there again, rural Taiwan might not be the same as rural England or rural elsewhere. Data from Western nations do point to 'urbanisation' as being a potential contributory factor in the increasing numbers being diagnosed with autism. Remember freeways (motorways in England) and autism? Bear also in mind that (a) where you currently live is not necessarily the same as where were you born or where your parents lived before you were born and (b) very few people tend to live in city centres, at least here in the UK; more often than not you get a doughnut effect in terms of residence being outside of a hollow built-up city centre.
That all being said I'm not ready to discount the current results as an artifact or fluke just yet. The study by Roberts and colleagues** published a few years back which suggested that pregnant women living close to sprayed fields had a six-fold increase in later offspring diagnosis of autism comes to mind. Having done a little bit of reading on the persistence and potential effects of things like pesticides, it is perhaps unwise to rule out any 'environmental' factor in relation to autism, at least some cases of autism, just yet. Certainly here in the UK, the potential health implications of pesticide exposure seems to still be on the research menu as per this study description by Galea and colleagues***. We await their findings.
[Update 15/02/12: Found the pin-mapping data we undertook. A poster presentation 'UK Autism Demographics' Budd, B. 2000: Autism: perspectives on progress. University of Durham. pp.207-214. Yes, proportionally more people with autism living in rural areas based on analysis of 784 people with autism in the UK (1996-2000)].
* Kiani R. et al. Urban–rural differences in the nature and prevalence of mental ill-health in adults with intellectual disabilities. Journal of Intellectual Disability Research. February 2012.
** Robert E. et al. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley. Environmental Health Perspectives. 2007; 115: 1482-1489.
*** Galea KS. et al. Biological monitoring of pesticide exposures in residents living near agricultural land. BMC Public Health. November 2011.
An important study was published a few months ago that examined the frequency of sperm mutations in workers at a benzene manufacturing plant in China. The study recruited 30 workers who had worked at the benzene manufacturing plant for more than a year and divided the workers into three groups, a low exposure group, a moderate exposure group and a high exposure group. The study included a control group of 11 unexposed workers from the same town.ReplyDelete
Every participant in all four groups was found to have de novo sperm mutations including 1p36 sperm mutations. The frequency of the sperm mutations was lowest, but present, in the unexposed group, higher in the low exposed group, higher still in the moderate exposed group and highest in the high exposed group. The 1p36 deletion syndrome is present in 1 in 5,000 to 10,000 newborns:
The 1p36 deletion syndrome is also associated with co-occurring autism:
This is the first study that has demonstrated a direct connection between a specific sperm mutation (1p36 deletion), a specific severe genetic syndrome (1p36 deletion syndrome) and a specific environmental pathogen (benzene).
The CHARGE group published a study a year ago that found that living in close proximity (<309m) to heavily congested freeways in California was associated with increased risk for autism. Benzene, because of its high octane number, is an important component in the production of refined gasoline and diesel fuels and one has to consider the possibility that at least some of these cases might be related to sperm mutations associated with long-lasting high exposure to benzene particles and other air borne environmental pathogens.
A very interesting association between MTHFR and chromosome 1p36 that you highlight (which I will be doing some more reading on).
There is some similar thinking on-going with regards to pesticide exposure and sperm mutations as per articles like this one: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1240505/pdf/ehp0109-001237.pdf and this one: http://toxicology.uga.edu/8930/op_and_sperm_motility.pdf
Without trying to be too controversial, the recent reports coming out about other products are also a concern: http://www.safefoodfoundation.org/57277946-RoundupandBirthDefectsv5.pdf
Some of these papers tally quite well with the rise of epigenetics.
Interesting articles, indeed. Does make one think.ReplyDelete
Hello friends -ReplyDelete
Regarding the CHARGE study with airborne pollutants as the suggested environmental candidate, a very graceful paper came out about the same time showing a dose relationship between polycyclic aromatic hydrocarbons, a highly replicated autism risk gene (MET-C), and "associated negative behavioral learning and memory outcomes".
Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase, MET
Full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2984527/?tool=pubmed
Many thanks for the link pD - very interesting indeed.ReplyDelete
I'm glad you introduced MET because I remember reading your post on MET and autism last year: http://passionlessdrone.wordpress.com/2011/02/25/autism-alphabet-soup-met-hgf-plaur-serpine/ as part of some interest on the recent Heuer paper: http://www.nature.com/tp/journal/v1/n10/full/tp201148a.html
I can't profess to be an expert on PAHs but from what I remember about Heuer, one of the main issues was the association between MET-C, foetal (sorry UK spelling) brain antibodies and a reduction in the anti-inflammatory cytokine, IL-10. Does this mean that outside of the MET-C SNP, PAHs have the same ability to influence protein levels with potential onward effects?
In the US the Environmental Protection Agency has accumulated statistics on the level of air pollution and the risk for health problems by state:ReplyDelete
The states with the highest risks are the states with the largest densly packed cities and urban areas (over one million). The states with the highest risks (4.00 index or higher) are New York, Washington DC, New Jersey and California. The states with the lowest risks (1.00 index or lower) are rural states that have no large cities and densely populated urban areas and are Wyoming, Iowa, South Dakota and North Dakota.
The CDC also reports on the prevelance of autism by state. The states with the highest prevelance rates for autism include New York, New Jersey and California all states with densly populated urban areas, the same states with the highest level of air polution and health problems by state. Iowa and Vermont have the lowest prevelance rates for autism and both are rural states with no densly populated urban areas.
It might also interest you that a BBC report (2005) found that in the capital of Iran, Tehran air pollution had reached a critical state, and Iranian authorities blamed the severe smog on the three million cars many of which lacked modern exhaust filters.
Thanks again RAJ for the link.ReplyDelete
Acknowledging that cars have got a little (a little only) cleaner in terms of their exhaust fumes, my mind wanders back to a few posts last year on the topic of lead and lead exposure. There was this post on a study from Saudi Arabia about lead exposure and autism: http://questioning-answers.blogspot.com/2011/07/even-superman-had-problems-with-lead.html alongside some speculation on reduced lead exposure potentially also being linked to a drop in the US crime figures: http://questioning-answers.blogspot.com/2011/06/us-crime-figures.html
I probably am cherry-picking slightly when it comes to air pollution and singling out lead, but nevertheless find it interesting.
It terms of the Iranian report, we also arrive at the various concerns on fine particulates in relation to health and in particular, nanoparticles: http://news.bbc.co.uk/1/hi/health/8091141.stm
As pd pointed out, the CHARGE study group is studying G/E interactions between specific environmental pathogens and genetic polymorphisms in the womb and in childhood. There are a number of groups that are recruiting thousands of families here in the US (CHARGE, MARBLES, EARLI) and in Europe (the ABC Cohort study group in association with Columbia University)) and they are all studying the neurotoxic effects on early brain development. What they are missing is that, as the Benzene study demonstrated, environmmental pathogens can possess genotoxic effects that can cause de novo sperm or egg mutations prior to conception.ReplyDelete
One of the puzzling questions facing autism researchers is why is advancing parental age associated with increased autism risk. The association with advancing parental age and increased autism risk is is one of the most replicated findings in autism research.
Several studies have been published in the field of evolutionary biology have tested the hypothesis that advancing age may be associated with increased frequency of sperm mutations in healthy volunteer donors. Bosch et al (2003) did indeed find that the frequency of chromosome 9 sperm mutations was found in all healthy donors segregated by age groups and does increase with advancing age. Sloter et al (2007) found that structural aberrations in chromosome 1 was present in the sperm of all volunteer donors and the frequency of sperm mutations significantly increased with advancing age. Klinefelter Syndrome is one of the most common mutations affecting 1 in 500-1,000 boys. The Klinefelter mutation is caused by a de novo mutation and is not inherited. Klinfelter Syndrome is associated with autism and may involve the neurexin–neuroligin genes (Bishop & Scerif 2011). Lowe et al (2001) examined the sperm of 38 fathers of Klinefelter boys and found the frequency of the XY sperm mutation is increased with advancing paternal age.
Could the increasing frequency of sperm mutations in advancing age be associated with long lasting exposure to genotoxic environmental pathogens, certainly a possiblity.
Sloter ED et al (2007). Frequency of human sperm carrying structural aberrations of chromosome 1 increases with advancing age. Fertil Steril. 2007 May;87(5):1077-86. Epub 2007 Apr 11.
Lowe et al (2001). Frequency of XY Sperm Increases with Age in Fathers of Boys with Klinefelter Syndrome. American Journal of Human Genetics 69(5) Nov 2001 1046-1054.
Bosch et al (2003). Linear increase of structural and numerical chromosome 9 abnormalities in human sperm regarding age. European Journal of Human Genetics (2003) 11, 754–759. doi:10.1038/sj.ejhg.5201049
Hi Paul Whiteley -ReplyDelete
That combo MET-fetal-brain-antigen paper is one that I've been thinking about writing about in detail. Really cool paper, ultimately I think that notions of a 'loss of tolerance' and extended states of inflammation are going to keep popping up. Very inconvenient.
Does this mean that outside of the MET-C SNP, PAHs have the same ability to influence protein levels with potential onward effects?
There do look to be functionally very similar effects, if your end point of interest is decreased MET expression.
Prenatal B(a)P exposure also downregulated Met RNA and protein levels and dysregulated normal temporal patterns of expression during synaptogenesis. Consistent with these data, transcriptional cell–based assays demonstrated that B(a)P exposure directly reduces human MET promoter activity.
They may also participate via a double hit; they have been shown to be inflammatory via increased ROS in the periphery and induce microglial activation (in vitro) (i.e.,http://www.ncbi.nlm.nih.gov/pubmed/20801209 and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848611/?tool=pubmed). Given that they also appear to be able to participate in a suppression of regulating the immune response through decreased MET expression, the analogy that seems appropriate is one of lighting both ends of the candle. Nice.
Many thanks pD. Will have a look through the reference.ReplyDelete
I believe autism is directly related to the age of the mother at the time of a babies birth. Inner city youth becoming young mothers in their 20s. 20 to have a baby is young today vs. older suburban and rural mothers that put a career first which would influence the results. If down syndrome is age related then why not other genetic problems? Brick New Jersey, the autism capital has an average age higher then most places. A 40 year old mother would have been a granny instead for most of man's historyReplyDelete
Many thanks for the comment Fred.ReplyDelete
An interesting hypothesis worthy of some follow-up given all the interest in parental age and risk of offspring autism.