"Zika Virus as a Possible Risk Factor for Autism"?

The paper by Vianna and colleagues [1] provides the blogging fodder today, discussing a potentially important topic around whether "the fetal brain infection caused by ZIKV [Zika virus] could predispose to ASD [autism spectrum disorder]."

Just before anyone gets the impression that a *link* has been found between Zika virus exposure and autism or autism spectrum disorder (ASD), I'm going to say no, not yet. The current peer-reviewed evidence at the time of writing this post has not identified autism as an outcome following exposure to the Zika virus. That's not to say that various other neurodevelopmental issues have not been associated with Zika virus exposure (see here for example) or that Zika virus exposure might not have biological consequences akin to that noted in some autism [2]. But as far as I'm aware, there is no peer-reviewed science yet suggesting that autism is for example, over-represented among those exposed to Zika virus in-utero. Not yet anyway.

Nonetheless, Vianna et al go through a number of lines of evidence suggesting how autism *could* be an outcome of Zika virus exposure. They start by talking about how Zika virus exposure during pregnancy can have a devastating effect on the developing child (see here) as a function of its teratogenic status. Severe microcephaly (small head size), a cardinal feature linked to infants' Zika virus exposure during pregnancy, has notable effects on the brain and its development, and is one of the more noticeable effects associated with Zika virus exposure in-utero. But further: "this phenotype is now considered only “the tip of the iceberg” and there is a spectrum of less severe abnormalities after congenital Zika infection."

Authors go on to talk about how pregnancy is a time of 'change' when it comes to maternal immune system functions, as a reprogrammed immune system has to become 'tolerant' of the developing foetus. Such reprogramming means that the foetus can survive and thrive. It also however means that the maternal immune system might be more susceptible to certain infections, where for example "opportunistic infections... take advantage." This is also the point where autism enters into the conversation, and the idea that exposure to various infections (viral and bacterial) occurring during pregnancy "can alter [offspring] brain development and are associated with alterations, such as brain calcifications, microcephaly, and neurodevelopmental disorders." I've covered a few possible examples on this blog with autism in mind (see here and see here).

Putting all this together, as well as talking about some of the immune system chemistry that *might* link Zika virus exposure and autism, and the authors come up with a model of 'neuroimmunomodulation' talking about "an ineffective anti-viral response" and increased levels of pro-inflammatory cytokines as being potentially important. I'll also provide another quote from Vianna which is similarly intriguing: "Moreover, in the case of ZIKV, previous infections with other flaviviruses, such as dengue virus and yellow fever, may trigger a secondary immune response of differential magnitude given the great molecular similarity of some immunogenic epitopes among these correlated viruses."

Reiterating that there is currently no link between Zika infection and risk of autism, I do find the Vianna paper interesting. It offers some testable hypotheses that could examined in the lab and beyond. It also provides some further support for the various surveillance and monitoring initiatives that remain in place with regards to Zika virus and the promise of further important data to come from them.

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[1] Vianna P. et al. Zika Virus as a Possible Risk Factor for Autism Spectrum Disorder: Neuroimmunological Aspects. Neuroimmunomodulation. 2019 Jan 10:1-8.

[2] Beys-da-Silva WO. et al. Zika Virus Infection of Human Mesenchymal Stem Cells Promotes Differential Expression of Proteins Linked to Several Neurological Diseases. Mol Neurobiol. 2018 Oct 30.

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Project TENDR and chemical exposures part 2: organophosphate pesticides aren't great for child health

So, without striking too many chords on the old 'we've been here before' piano, consider this post an extension of some other discussions a while back suggesting that exposure to some classes of 'chemicals' might not be particularly great for child health (see here).

The findings reported by Irva Hertz-Picciotto and colleagues [1] continue the Project TENDR theme with their assertion that there is "compelling evidence" that prenatal exposure to organophosphate (OP) pesticides "is putting children at risk for cognitive and behavioral deficits and for neurodevelopmental disorders." Their observations have also been picked up by the lay media with some striking headlines like 'Ban entire pesticide class to protect children's health, experts say' complete with the required stock photo of crops being sprayed from the air.

Organophosphate (OP) compounds such as OP pesticides have a very mixed history. As well as being the insecticide of choice in many countries as a result of their excellent pest control profile, the organophosphate chemistry has also been utilised for less desirable purposes as per its classification as a component of nerve agents. Remember all the quite recent chatter about a nerve agent called Novichok? Well, the chemistry behind Novichok apparently has a very distinctive OP "structural backbone" [2]. That's not to say that every OP pesticide is Novichok. But rather that the activity of OPs specifically targeting the action of acetylcholinesterase (AChE) enzymes, important enzymes that are required for proper nerve function, is also an important biological action of various nerve agents. This in itself would suggest caution in the use of OPs.

The Hertz-Picciotto paper (policy forum) is pretty data heavy in terms of how much OP pesticides are used across the globe, the slew of mostly observational research studies that have looked at pesticide exposure and various neurodevelopmental variables and the concerns voiced at both high and low levels of OP pesticide exposure. They make a few recommendations: better training for health professionals on the potential risks attached to OP pesticide exposure, greater moves to switching to "nontoxic approaches to pest control" and perhaps most controversially: "Governments phase out chlorpyrifos and other OP pesticides."

The caveats? Well I might mention a few, minus any charges of me somehow 'standing up for OPs'. First, I don't think it's unreasonable to suggest that children in particular, do need to be more strongly protected against pesticides that are (chemically-speaking) not a million miles away from nerve agents. As the authors mention, there is quite a bit of evidence in the peer-reviewed literature to suggest a possible *association* between pesticide exposure and diagnoses such as autism (see here and see here) or beyond (see here). The thing is that like many other non-genetic environmental factors (e.g. air pollution) *linked* to a heightened risk of autism or other neurodevelopmental labels, it's more about environment + genetics when it comes to risk (see here) rather than environment just working on its own. We need for example, to know more about the ways and means that OPs are metabolised in the body and whether there could be some interesting biochemistry potentially linked to labels like autism (see here).

Second, some thought needs to go into the possible replacements if OP pesticides were to be banned outright. Thinking back to a post not-so-long-ago talking about DDT exposure and offspring autism (see here) I was struck by how short some memories are in terms of why such products were developed in the first place. I don't think anyone would seriously contemplate that the development of OP pesticides was anything more than to stop pests attacking crops and to maintain yields that can feed the population. These compounds were developed with good intentions. Obviously, as the research literature has grown, we have come to realise that such products are not side-effect free and more stringent controls have been put into place regarding safety. But to ban them outright is not something that can be done overnight. What do we replace them with? Do we just accept that crop yields will be lower and less food will be produced? Do we instead start thinking about other ways to make crops more resistant to the pests that blight them? That last question has already had its own 'issues'.

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[1] Hertz-Picciotto I. et al. Organophosphate exposures during pregnancy and child neurodevelopment: Recommendations for essential policy reforms. PLoS Med 15(10): e1002671.

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"a neurodevelopmental abnormality possibly associated with congenital Zika virus infection"

I'm a little late getting to the findings reported by Marion Rice and colleagues [1] (open-access available here) but I did want to cover them because of their current importance and perhaps future implications. The topic in question was the Zika virus and specifically the research efforts of the U.S. Zika Pregnancy and Infant Registry (USZPIR) used to track those infants exposed to the virus during the important nine months than made them. Just in case you didn't follow the hows-and-whys of the Zika virus outbreak and its effects a while back, some background can be found here.

Rice et al report findings for nearly 1500 children "of mothers with laboratory evidence of confirmed or possible Zika virus infection during pregnancy" in terms of their level of care and clinical follow-up and also "to identify Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital Zika virus infection." Aside from reporting that the majority of their cohort had "some follow-up care reported" ('some' that included very basic "length/height, weight, or head circumference measurements and date of measurements" reported back to the USZPIR), a few other observations were also made. This included findings such as: "approximately one in seven (14%) were identified during infancy or early childhood as having either a Zika-associated birth defect, a neurodevelopmental abnormality possibly associated with congenital Zika virus infection, or both."

Although the talk about birth defects is important to Zika virus exposure (microcephaly being only one part of this), I was specifically interested in the 'neurodevelopmental' side of things reported in the Rice paper as affecting 9-10% of the cohort depending on what laboratory testing for Zika virus exposure was carried out. Bearing in mind the age group of the cohort (1 year old and above), and that such neurodevelopmental issues covered a lot of clinical ground (e.g. "hearing abnormalities; congenital contractures; seizures; body tone abnormalities; movement abnormalities; swallowing abnormalities; possible developmental delay; possible visual impairment; and/or postnatal-onset microcephaly") it's important to understand how infections such as Zika might have the ability to affect cognitive and/or neurodevelopmental outcomes. What's also important too is the realisation that given the young age of the cohort, "the full spectrum of adverse outcomes related to congenital Zika virus infection is not yet known." So developmental delay for example, *could* eventually develop into something else, and why appropriate monitoring will continue through initiatives like the USZPIR.

From a cold, objective science perspective and without wishing to diminish the very human effects associated with this event, the 2016 Zika outbreak that struck the Americas provides an ideal opportunity to study our important interaction with the environment around us. It emphasises how facets of our environment can very much influence both physical and psychological health, particularly at critical times of development. A lesson that perhaps is transferable to many different neurodevelopmental labels [2]...

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[1] Rice ME. et al. Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection - U.S. Territories and Freely Associated States, 2018. MMWR Morb Mortal Wkly Rep. 2018 Aug 10;67(31):858-867.

[2] Lydholm CN. et al. Parental infections before, during and after pregnancy as risk factors for mental disorders in childhood and adolescence – a nationwide Danish study. Biological Psychiatry. 2018. Oct 1.

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