"Low parental melatonin levels could be one of the contributors to ASD and possibly ID etiology"

The title heading this post - "Low parental melatonin levels could be one of the contributors to ASD and possibly ID etiology" - comes from the findings reported by Wiebe Braam and colleagues [1]. It continues a research theme on the topic of melatonin and autism or autism spectrum disorder (ASD) (and intellectual disability, ID) (see here).

Perhaps most famously known for its links to circadian rhythms, melatonin is quite an important topic in many areas of autism research and practice. The use of melatonin to influence various sleep issues that seem to be quite regularly present in relation to autism (see here) takes the lion's share of the limelight (see here) but this is a compound potentially doing sooo much more. I've for example, talked about melatonin in relation to intestinal permeability issues (see here) on this blog, as this molecular handyperson [2] offers several possible links/effects with other biological systems. Indeed, Braam et al start from a position where melatonin "is important for normal neurodevelopment and is highly effective in protecting DNA from oxidative damage" continuing an interest for members of the authorship group.

The current findings have, I believe, been seen before on the preprint server bioRxiv [3] so we knew this peer-reviewed publication was coming. Including urine samples from 60 mothers of children diagnosed with autism and a somewhat smaller number from control mothers (with no children diagnosed with autism), researchers submitted said urine samples to analysis for a compound called 6-sulfatoxymelatonin, a primary urinary metabolite of melatonin. I understand that the gold-standard analytical method that is mass spectrometry was the chosen way to determine urinary 6-sulfatoxymelatonin, so one has some confidence that researchers were detecting/measuring this metabolite pretty accurately.

Researchers reported that levels of urinary 6-sulfatoxymelatonin were lower in mums of children diagnosed with autism compared to controls. This finding mirrors that reported in young people with autism [4] and, on more than one research occasion [5]. It looks like there may be a familial element to some of the issues with melatonin which quite neatly fits into other work suggesting similar things with other biological systems including that intestinal permeability [6] that I just mentioned.

Insofar as the implications and 'where next?' questions arising from such work, they are potentially numerous. The relationship with sleep and circadian rhythms is an obvious starting point. Further exploration of whether maternal melatonin biochemistry could be a *risk* factor for similarly altered biochemistry in relation to offspring with autism is also indicated. I'd also like to see some data on paternal and sibling levels of compounds such as 6-sulfatoxymelatonin too (and their related compounds) and how that might correlate with issues such as sleep in those populations.

The inclusion of the word 'sulfate' in 6-sulfatoxymelatonin might also lead to another area of possible research inspection with autism in mind. I hark back to work conducted seemingly aeons ago talking about how sulfate/sulphate chemistry might show some connection to some autism (see here). Sulfation is an important part of the reaction forming 6-sulfatoxymelatonin: 6-hydroxylation --> 6-hydroxymelatonin --> 6-sulfatoxymelatonin (I think), which would be reliant on there being enough sulphate to successfully produce such a reaction on a suitably large scale.

And finally, minus scaremongering or any sweeping generalisations, I do wonder whether further research needs to be done in a wider context of low urinary 6-sulfatoxymelatonin levels. I speak for example of research such as that by Devore and colleagues [7] talking about "Higher urinary melatonin levels... suggestively associated with a lower overall risk of breast cancer." This, in the context that such health issues have been reported with autism mentioned (see here); something which also requires a lot more scientific investigation...

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[1] Braam W. et al. Low maternal melatonin level increases autism spectrum disorder risk in children. Research in Developmental Disabilities. 2018. March 1.

[2] Boga JA. et al. Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman"? Rev Med Virol. 2012 Sep;22(5):323-38.

[3] Braam W. et al. Low parental melatonin levels increases autism spectrum disorder risk in children. bioRvix. 2016. April 2.

[4] Tordjman S. et al. Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder. Psychoneuroendocrinology. 2012 Dec;37(12):1990-7.

[5] Tordjman S. et al. Nocturnal excretion of 6-sulphatoxymelatonin in children and adolescents with autistic disorder. Biol Psychiatry. 2005 Jan 15;57(2):134-8

[6] de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24.

[7] Devore EE. et al. Urinary Melatonin in Relation to Postmenopausal Breast Cancer Risk According to Melatonin 1 Receptor Status. Cancer Epidemiol Biomarkers Prev. 2017 Mar;26(3):413-419.

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