The results of a newly reported study in mice by scientists at Duke University support naval oceanographer Carina Block’s notion that the jet exhaust fumes she and her fellow female sailors were regularly exposed to, combined with unavoidable job stress, were leading to adverse health outcomes for their children. The study findings indicate that air pollution, alongside housing insecurity during pregnancy, lead to autism-like social behavior and altered wiring in the brains in male, but not female, pups. The results also suggest that the immune system is at fault in the development of these neurodevelopmental disorders (NDDs).
“I was pregnant, stressed, and worked near planes,” Block recalled. “I walked past jet fuel exhaust every day. And my child ended up developing a neurodevelopmental disorder, hydrocephalus.” While Block’s daughter is now thriving, the study by Block and colleagues, published in Cell Reports, provides evidence that had Block been gestating a son, he may have been born with autism. Block, together with Duke University psychology and neuroscience professor Staci Bilbo, PhD and cell biology professor Cagla Eroglu, PhD, are co-authors of the team’s published paper, which is titled, “Prenatal environmental stressors impair postnatal microglia function and adult behaviour in males.” In the study the team concluded, “ … our findings provide an important first step toward revealing the non-genetic causes for NDDs so that preventative and therapeutic approaches can be developed along with informed policy changes.”
Air pollution such as exhaust emitted by diesel engines in trucks, is linked to increased rates of neurodevelopmental disorders such as schizophrenia and autism, the authors noted. “The incidences of neurodevelopmental disorders (NDDs) have been increasing in recent decades, suggesting a role for non-genetic environmental factors,” they wrote in their paper. “Furthermore, sex is a significant risk factor for these disorders, with a strong male bias. Air pollutant exposure during pregnancy or the first year of life is one of the most consistent environmental risk factors for NDDs.”
But while the 99% of people across the globe live in cities with unhealthy air, only one in every 44 children is diagnosed with autism, and four times more boys than girls. So why doesn’t everyone develop autism? “Environmental toxins are worse for some people than for others and it’s always the most vulnerable populations that are affected,” Bilbo said. In the case of autism and air pollution, Bilbo thinks the missing link is maternal stress stemming from poverty and housing insecurity. “It’s not that wealthy people aren’t stressed,” Bilbo said. “But it’s different when you have to worry about where you’re going to live and whether you’re safe in your home.”
While there are existing data in humans supporting Bilbo’s claim, it’s impossible, and unethical, to directly test these ideas in pregnant women with a view to identifying any biological mechanisms by which air pollution and stress might combine to rewire the brains of developing children. Block and her team instead exposed pregnant mice to the poor housing and air quality conditions that many people endure every day, and looked at how their offspring fared.
As a proxy for air pollution, the mouse mothers were exposed to diesel exhaust particles. As an additional stressor, towards the end of their pregnancy, the female mice were allotted less building materials than usual with which to construct nests for their pups, effectively representing insufficient housing.
The study results confirmed that the stressed moms remained excellent parents, in that they nursed and groomed their pups just as much as the mouse mothers who were spared from prenatal stressors. However, while the female pups born to stressed and pollutant-exposed mothers grew up as expected, the male pups misread social cues throughout life. In one set of experiments it was shown that as teenagers, these males preferred hanging out with a yellow rubber duck than with a nearby mouse (mice usually prefer the company of one of their own rather than a bath toy).
Block and her team then investigated whether the male pups’ brains had been rewired early on, leading to shyer male teens. Specifically, the research team wondered if the male brains didn’t get their necessary refinement early in development.
Early in life, all animals are born with an overabundance of brain cell synapses, which are pared down as the animal grows. The synapses leading to successful tasks, like picking up a glass, are maintained and strengthened, whereas the connections that lead to failed attempts get removed. “In early postnatal brain development, an exuberant period of synaptogenesis is closely followed by and overlaps with a period of synaptic pruning, where weak or unnecessary synapses are eliminated,” the scientists stated.
The team’s studies showed that stressed moms who had inhaled diesel fumes gave birth to male pups who, as toddlers, appeared to miss this synapse organization in the anterior cingulate cortex (ACC), a brain region important for perceiving and producing social cues. An overabundance of synapses in this region of the male pups’ brains seemed to explain their shy social tendencies as teenagers, but this then also left open the question of how the smog and stress during pregnancy halted typical brain sculpting.
To investigate this more closely Block and her team looked at the immune system, and specifically at immune cells in the brain called microglia. Microglia monitor for bacteria and viruses, but they are also on the alert for weak or dead synapses, which they readily remove to help tidy up the brain. “Microglia are the primary immunocompetent cells of the brain and are exquisitely sensitive to perturbations of homeostasis and thus may be poised to act as immediate responders to environmental insults,” the team noted. “Microglia are also essential regulators of activity-dependent synaptic remodeling during development, in which they prune inappropriate/weak synapses while sparing appropriate/strong connections.”
Block reasoned that if there were more synapses than usual in the brains of male pups born to stressed and pollution-exposed mothers, then perhaps there might also not be as many microglia in the brains of affected males. In fact, the team noted, “ … we and others have found sex differences in microglial development, maturation, and function, including an increased relative expression of microglial genes in male brains, compared with females. Interestingly, the microglial genes enriched in male brains are also implicated in ASD.”
However, and surprisingly, Block and colleagues found that adolescent males from stressed moms had just as many microglia in the ACC as did their peers from non-stressed moms. But smog and housing stress was associated with microglia having less of the protein that stimulates their appetite for synapses, and this could likely explain the abundance of synapses.
Interestingly, by adulthood, the situation seemed to reverse. Male mice born to smog- and stress-exposed mothers now had fewer synapses in their ACC and were more gregarious than their unexposed peers. This atypical tendency to be more outgoing rather than reserved mirrored the behavior and brain activity of mice with autism-linked genes recently described by Block’s collaborator and co-author, Duke neurobiology professor and psychiatrist Kafui Dzirasa, MD, PhD.
People with autism are often mistakenly assumed to be less social, but Block shared that, “If you’ve met one person with autism, then you’ve met one person with autism.” Dzirasa added that many of his patients with autism would fail the standard lab tests used to diagnose mice, which essentially pigeon-holes rodents as autism-like if they have less inclination to socialize. Instead, Dzirasa and Block say that for people with autism, it’s more of a misunderstanding of social cues and conventions rather than being inherently introverted.
Block and Bilbo suggest that their new work provides a clear mechanism in mice that may explain why high levels of air pollution increases the likelihood a child will develop autism only if they’re born in a poor neighborhood. It might also provide insights that could one day lead to the development of drugs that help to prevent microglia from being manipulated by environmental stressors, since diesel exhaust and housing stress triggers a similar immune response when pregnant women catch the flu.
For now, Bilbo and her team hope that their newly reported evidence about the impact of stress and air pollution during pregnancy might push policymakers to promote legislation supporting clean air initiatives and social services, such as improved and expanded public housing. “You can’t ignore this study’s mechanistic findings,” Bilbo said. “This is happening, and this is how.”
Acknowledging limitations of their study, the authors concluded, “Our findings elucidate a mechanism by which environmental pollutants can synergize with psychosocial stress in pregnant mothers and induce MIA, which has specific long-term effects on the development and function of male brains. This is particularly concerning, now more than ever, because ongoing climate change caused by increased economic activity and reduced environmental protection enforcements have led to a rapid worsening of air quality in recent years. Heightened air pollution is likely to synergize with social stressors in vulnerable populations, causing further disparities in the well-being of future generations.”