passionless Droning about autism

Hello friends –

One of the more beautiful and terrifying concepts I’ve come across in the last year or so is the idea of ‘developmental programming’, or sometimes fetal programming, or as I imagine it will eventually be recognized, the realization of subtle change is still change, and subtle change during critical timeframes can amplify into meaningful outcomes.  The underlying hypothesis is that environmental influences during early life, gestation, infancy, or even childhood, have the capacity to permanently influence physiological and behavioral state into adulthood.  The available evidence implicates the potential for developmental programming to be involved with an assortment of conditions that on the whole, you’d rather not have than have, including the spectrum sized set of disorders grouped as ‘metabolic syndrome’ that incorporates several risk factors for cardiovascular disorders, obesity, type II diabetes.  There is also less pronounced evidence for some autoimmune disorders, and perhaps, autism. 

Here is the most concise explanation of developmental programming I’ve seen so far, from Developmental Programming of Energy Balance and Its Hypothalamic Regulation

The concepts of nutritional programming, fetal programming, fetal origins of adult disease, developmental origins of health and disease, developmental induction, and developmental programming were all conceived to explain the same phenomenon: a detrimental environment during a critical period of development has persistent effects, whereas the same environmental stimulus outside that critical period induces only reversible changes.

I am absolutely in love with the importance of time dependent effects, a sort of combo pack of why the dose doesn’t always make the poison, and the importance of understanding subtle interactions in developing systems. 

The area of developmental programming that has a ton of research in the human field and animal models is the link between metabolic syndrome and a differently structured uterine and/or early postnatal environment.  A nice review from 2007, Developmental programming of obesity in mammals (full paper) has this:

Converging lines of evidence from epidemiological studies and animal models now indicate that the origins of obesity and related metabolic disorders lie not only in the interaction between genes and traditional adult risk factors, such as unbalanced diet and physical inactivity, but also in the interplay between genes and the embryonic, fetal and early postnatal environment. Whilst studies in man initially focused on the relationship between low birth weight and risk of adult obesity and metabolic syndrome, evidence is also growing to suggest that increased birth weight and/or adiposity at birth can also lead to increased risk for childhood and adult obesity. Hence, there appears to be increased risk of obesity at both ends of the birth weight spectrum.

And

Childhood and adult obesity are amongst the cardiovascular risk factors now considered to be ‘programmed’ by early life and, perhaps counter-intuitively, babies subjected either to early life nutritional deprivation or to an early environment over-rich in nutrients appear to be at risk. Supportive evidence includes the observation of a ‘U-shaped’ curve which relates birthweight to risk of adult obesity (Curhan et al. 1996).

[Check out that example of a hormetic dose curve!  Totally sweet!]

The list of papers supporting a link between abnormal gestational or birth parameters and subsequent obesity in the offspring is very, very voluminous.   The satellite level high view of the research starts with Dutch mothers during a time of famine, and the observations that these children were much more likely to be obese at nineteen in Obesity in young men after famine exposure in utero and early infancy.  Later, infants in England were found to have birth weight positively correspond to adult weight in Birth weight, weight at 1 y of age, and body composition in older men: findings from the Hertfordshire Cohort Study (full paper).  A study with twin pairs, Birth weight and body composition in young women: a prospective twin study  had similar findings, but with the additional coolness factor of being able to detect differences between genetically identical twins who happened to be born at different weights.  There are studies on infants that are born light but then ‘catch up’are consistently more likely to be obese, a review of which can be found in Rapid infancy weight gain and subsequent obesity: systematic reviews and hopeful suggestions.  Startlingly, Weight Gain in the First Week of Life and Overweight in Adulthood observed that formula fed babies who gained considerable weight during the first eight days after birth were more likely to be obese as adults, similar to other findings implicating formula fed babies with adult obesity.

Therearealsoconservativelya bazillionanimalmodelsthattellusthatthestudiesin humans are accurate.

Part of me hates the deterministic nature of these findings, it’s really just an extension of the fatalism of genetic assignment, but on the other hand, the data is the data.  I must admit, I am in love with the underlying evolutionary cleverness of the thrifty phenotype end of the U curve on display; a fetus or neonate that is deprived of nutrients, or perhaps, some types of nutrients, programs itself for an environment in which food is scarce, handling calories differently at a very fine grained metabolic level.  From a survival standpoint this modification is most definitely the smart move; all inbound indicators are signaling to the fetus that calorie acquisition is going to be tough on the outside, and as a result, the physiology is tweaked so that baby is ready to make the absolute most of any available nutrients.  If that child, however, is raised in a world with plentiful calories, if not always, beneficial calories, they tend to store fat more readily than a baby/child/adult that did not receive the same messages in utero.  Neat.

Like lots of things I seem to be running into, our observations of what is happening seem to be more advanced than our understanding of how it is happening.  The ideas of developmental programming have been around for a while, but we are still very much in the learning phase regarding mechanism of action, a very thorough review that I ran into can be found here:  Mechanisms of developmental programming of the metabolic syndrome and related disorders.   (full paper). 

Another example of programming a bit closer to home to the autism world has been in the news lately, namely the replication of findings that children who grow up around farm animals, or in some cases, pets, are less likely to suffer from allergies and /or asthma than children who grow up without that exposure.  These findings are also very robust, and appear to implicate similar critical developmental timeframes including the gestational environment, infancy, and toddlerhood. 

Here is an example of the kind of thing in this area,  Farming environment and prevalence of atopy at age 31: prospective birth cohort study in Finland

Cross-sectional studies have shown an association between the farming environment and a decreased risk of atopic sensitization, mainly related to contact with farm animals in the childhood. Objective Investigate the association of a farming environment, especially farm animal contact, during infancy, with atopic sensitization and allergic diseases at the age of 31. Methods In a prospective birth cohort study, 5509 subjects born in northern Finland in 1966 were followed up at the age of 31. Prenatal exposure to the farming environment was documented before or at birth. At age 31, information on health status and childhood exposure to pets was collected by a questionnaire and skin prick tests were performed. Results Being born to a family having farm animals decreased the risk of atopic sensitization [odds ratio (OR) 0.67; 95% confidence interval (CI) 0.56-0.80], atopic eczema ever (OR 0.77; 95% CI 0.66-0.91), doctor-diagnosed asthma ever (OR 0.74; 95% CI 0.55-1.00), allergic rhinitis at age 31 (OR 0.87; 95% CI 0.73-1.03) and allergic conjunctivitis (OR 0.86; 95% CI 0.72-1.02) at age 31. There was a suggestion that the reduced risk of allergic sensitization was particularly evident among the subjects whose mothers worked with farm animals during pregnancy, and that the reduced risk of the above diseases by farm animal exposure was largely explained by the reduced risk of atopy. Having cats and dogs in childhood revealed similar associations as farm animals with atopic sensitization. Conclusion and Clinical Relevance Contact with farm animals in early childhood reduces the risk of atopic sensitization, doctor-diagnosed asthma and allergic diseases at age 31.

That is one hell of a long running study and the findings are consistent with a wealth of similar studies across populations, including Exposure to environmental microorganisms and childhood asthma, and Effect of animal contact and microbial exposures on the prevalence of atopy and asthma in urban vs rural children in India.  These findings are part and parcel with the Hygiene Hypothesis, the idea that a relative reduction in ‘training’ of the immune system can lead to disturbances in normal immune system development and consequent development of autoimmune disorders.   (Here’s a nice review of the evidentiary backing for the Hygiene Hypothesis) From a clinical viewpoint, there are reasons to suspect this is a biologically plausible pathway; in Environmental exposure to endotoxin and its relation to asthma in school-age children the researchers reported an inverse relationship between the amount of endotoxin (i.e., a bacterial fingerprint that is recognized by the immune system) and the immune  response, stating, “Cytokine production by leukocytes (production of tumor necrosis factor alpha, interferon-gamma, interleukin-10, and interleukin-12) was inversely related to the endotoxin level in the bedding, indicating a marked down-regulation of immune responses in exposed children.”  We can also see immunomodulatory effects of farm or rural living in the cytokine profiles of breast milk between two populations, as reported in Immune regulatory cytokines in the milk of lactating women from farming and urban environments, which found much higher concentrations of TGF-Beta1, a critical immune modulator, in breastmilk and collustrum of ‘farm mothers’.  The concentration of TGF-Beta1 in breastmilk had already been implicated in infant development of atopic disease in Transforming growth factor-beta in breast milk: a potential regulator of atopic disease at an early age. 

The evidence supporting developmental programming in these instances is very problematic to overcome, clearly there are mechanisms by which the events of very early life can cause persistent changes to physiology into adulthood; be they changes ‘designed’ to be adaptive, or disturbed trajectories of usually tightly regulated systems that find inappropriate targets in an environment different than what our ancestors evolved in.  I’d note that none of what is above invalidates any findings of genetic involvement with cardiovascular problems, obesity, or asthma, but it should serve as a portrait of how genetic recipes are only part of the process. 

So, what about autism?  This is, admittedly, where things get a bit more speculative, there isn’t the same type of epidemiological evidence in the autism arena as what we see above.  Part of this discrepancy is an artifact of the fuzzy nature of autism, a bazillion different conditions each with their own personalized manifestation, a much more daunting set of variables to detangle compared with measuring BMI, triglyceride levels or asthma.  Those caveats in place, there is still room to discuss some potential examples wherein early life experiences might be participating in ‘programming’ some of what we see in autism. 

A nice review paper that speaks directly towards a developmental programming model that involves autism is Early life programming and neurodevelopmental disorders that includes as an author, Tom Insel, head of the National Institute of Mental Health, and generally, one of the good guys.   This is part of the abstract.

Although the hypothesized mechanisms have evolved, a central notion remains: early life is a period of unique sensitivity during which experience confers enduring effects. The mechanisms for these effects remain almost as much a mystery today as they were a century ago (Insel and Cuthbert 2009). Recent studies suggest that maternal diet can program offspring growth and metabolic pathways, altering lifelong susceptibility to diabetes and obesity. If maternal psychosocial experience has similar programming effects on the developing offspring, one might expect a comparable contribution to neurodevelopmental disorders, including affective disorders, schizophrenia, autism and eating disorders. Due to their early onset, prevalence and chronicity, some of these disorders, such as depression and schizophrenia, are among the highest causes of disability worldwide (World Health Organization, 2002). Consideration of the early life programming and transcriptional regulation in adult exposures supports a critical need to understand epigenetic mechanisms as a critical determinant in disease predisposition.

A concise explanation of the concept of developmental programming and the need for more finely detailed understandings of the likely epigenetic underpinnings.  Also included is a discussion of things like maternal stress during gestation, childhood environmental enrichment (or more specifically, ‘de-enriched’ or otherwise, terrible situations), and prenatal infection models.  Nice.  

What about specifics for the autism arena?  One environmental event that most everyone agrees can increase risk of an autism diagnosis is an immune challenge in the gestational period.  The animal models are robust and have been replicatedacross laboratories and epidemiological data supports an association.  A lot of groups have been studying the effects of maternal immune activation in animal models the past few years, what we can see are some striking parallel veins to what is observed in autism that involve the concept of developmental programming. 

One paper, with a title I love, is  Neonatal programming of innate immune function.  Here is a snipet of the abstract from the first paper:

There is now much evidence to suggest that perinatal challenges to an animal’s immune system will result in changes in adult rat behavior, physiology, and molecular pathways following a single inflammatory event during development caused by the bacterial endotoxin lipopolysaccharide (LPS). In particular, it is now apparent that neonatal LPS administration can influence the adult neuroimmune response to a second LPS challenge through hypothalamic-pituitary-adrenal axis modifications, some of which are caused by alterations in peripheral prostaglandin synthesis. These pronounced changes are accompanied by a variety of alterations in a number of disparate aspects of endocrine physiology, with significant implications for the health and well-being of the adult animal.

Another very cool, and very dense, paper with a salient title and content by the same group is  Early Life Activation of Toll-Like Receptor 4 Reprograms Neural Anti-Inflammatory Pathways (full paper) which reports that a single early life immune challenge results in persistently altered response to immune stimulants into adulthood, with differential responses in the CNS compared to the periphery.  Especially interesting in this paper is that the researchers have dug down a layer into the biochemical changes affected by early life immune challenge and found that alterations to HPA-Axis metabolites are responsible for the changes. 

Tinkering around with the HPA-Axis, an entangled neuroendicrine system that touches on stress response, immune function, mood, and more can have a lot of disparate effects.  It turns out, there is evidence that early life immune challenges can also modify behaviors in a way consistent with altered stress responses.

For example, the very recently published Peripheral immune challenge with viral mimic during early postnatal period robustly enhances anxiety-like behavior in young adult rats has a short, but to the point abstract:

Inflammatory factors associated with immune challenge during early brain development are now firmly implicated in the etiologies of schizophrenia, autism and mood disorders later in life. In rodent models, maternal injections of inflammagens have been used to induce behavioral, anatomical and biochemical changes in offspring that are congruent with those found in human diseases. Here, we studied whether inflammatory challenge during the early postnatal period can also elicit behavioral alterations in adults. At postnatal day 14, rats were intraperitoneally injected with a viral mimic, polyinosinic:polycytidylic acid (PIC). Two months later, these rats displayed remarkably robust and consistent anxiety-like behaviors as evaluated by the open field/defensive-withdrawal test. These results demonstrate that the window of vulnerability to inflammatory challenge in rodents extends into the postnatal period and offers a means to study the early sequelae of events surrounding immune challenge to the developing brain.

The methodology is very similar to what we see in a lot of animal models of early life immune activation, convince a young animals immune system that they are under microbial attack by mimicking either bacterial or viral invaders, and then measure behaviors, or physiology, later in life. This study could be seen as a complement to a much earlier (2005) paper, Early life immune challenge–effects on behavioural indices of adult rat fear and anxiety, which used a different immune stimulant (bacterial fingerprint/LPS versus viral fingerprint/Poly:IC), but which found generally consistent results.

There are more, for example, Early-Life Programming of Later-Life Brain and Behavior: A Critical Role for the Immune System (full paper), which reviews animal study evidence that early life immune challenges can have lifelong effects.  Here is part of the Introduction:

Thus, the purpose of this review is to: (1) summarize the evidence that infections occurring during the perinatal period can produce effects on brain and subsequent behavior that endure throughout an organism’s life span, and (2) discuss the potential role of cytokines and glia in these long-term changes. Cytokines are produced within the brain during normal brain development, but are expressed at much higher levels during the course of an immune response. In contrast to overt neural damage, we present data indicating that increased cytokine exposure during key periods of brain development may also act as a “vulnerability” factor for later-life pathology, by sensitizing the underlying neural substrates and altering the way that the brain responds to a subsequent immune challenge in adulthood. In turn, this altered immune response has significant and enduring consequences for behavior, including social, cognitive, and affective abilities. We discuss the evidence that one mechanism responsible for enduring cytokine changes is chronic activation of brain microglia, the primary immunocompetent cells of the CNS.

Check that out!  We have several papers showing, indeed, a ‘chronic activation of brain microglia’ in the autism population; one way, it seems, to achieve this, is ‘increased cytokine exposure during key periods of brain development’.  (Ouch!) 

Is developmental programming the mechanism by which gestational immune activation raises the risk of autism?  I don’t think we can answer that question with any authority yet, but the logical jumps to arrive at that conclusion are small, and  are supported by a great deal of evidence.  No doubt, we’ll be learning more about this in the years to come.

Ultimately, I think what all of this means is that, as usual, there is another layer of complexity thrown into the mix.  As far as autism goes, it seems likely that at least some of our children are manifesting behaviors consistent with autism as a result of things that happened to them very, very early in their life.  Figuring out if this is happening, how it is happening, and to which individuals, is a daunting, very difficult task; but at least we are approaching a level of knowledge to allow for such an endeavor.

This posting focused on the bad stuff, but the inverse is just as meaningful, having a ‘normal’ gestational period as far as nutrients go, programs you towards a more healthy weight, and being born to a mother exposed to a variety of microbial agents, as the overwhelming majority of mothers were for most of human existence, programs you away from asthma.  But from a broader standpoint, from a ‘every human on the planet’ view, I think we must begin to recognize that everyone is being programmed, in some ways for good, in others, for not so good.  Curiosity and thoughtful analysis is our way to illuminate the beautiful and dispassionate gears that propel the machinations of nature; developmental programming is one of the cogs in the natural world, hopefully, one day, we will acquire the wisdom to refine the program for our benefit, but in the meantime, it is still exciting to witness the discovery of the inner workings.

–          pD