Air pollution and stress alter the brain and social behavior of male mice

DURHAM, North Carolina — Naval oceanographer Carina Block had a hunch that the jet exhaust that she and her fellow sailors were regularly exposed to, combined with unavoidable job stress, was causing adverse health effects of their children. A new mouse study confirms Block’s suspicions, finding that air pollution as well as housing insecurity during pregnancy leads to autistic-like social behavior and differently wired brains in male puppies, but not female. The immune system seems to be involved.

“I was pregnant, stressed out, and working near planes,” Block recalled. “I walked past the kerosene exhaust every day. And my child ended up developing a neurodevelopmental disorder, hydrocephalus.

Block’s daughter is now thriving, as is Block, who is now Dr. Block after earning her Ph.D. at Duke University in the Psychology and Neuroscience Laboratories, Professor Staci Bilbo, PhD, and Cagla Professor of Cell Biology Eroglu, PhD. However, Block’s new post in the August 2nd edition of Cell Reports provides compelling evidence that if she had had a son in the making, he might have been born with autism.

Air pollution, such as the exhaust emitted by diesel truck engines, is linked to increased rates of neurodevelopmental disorders, such as schizophrenia and autism. While 99% of people on the planet live in cities with unhealthy air, only one in 44 children is diagnosed with autism (and four times as many boys as girls).

So why doesn’t everyone develop autism?

“Environmental toxins are worse for some people than others and it’s always the most vulnerable populations that are affected,” Bilbo said. In the case of autism and air pollution, Bilbo believes the missing link is maternal stress resulting from poverty and housing insecurity.

“It’s not that rich people aren’t stressed out,” Bilbo said. “But it’s different when you have to worry about where you’re going to live and whether you’re safe at home.”

While there is compelling human data to support Bilbo’s claim, it is impossible (and unethical) to directly test these ideas in pregnant women in order to uncover the biological mechanism by which air pollution and stress can conspire to rewire the brains of developing children.

To fill this gap, Block and his team exposed pregnant mice to the poor housing and air quality conditions that many people endure every day and examined the condition of their offspring.

As an indicator of air pollution, mouse mothers were exposed to diesel exhaust particles, the unseen but pernicious polluting semi-trucks and construction machinery regularly discharged. Towards the end of their pregnancies, the mother mice faced another stressor: inadequate housing. Pregnant mice were given fewer building materials than usual to build their nests with their young.

Despite all of this, the stressed mothers were still stellar parents – they nurtured and nurtured their puppies just as much as those who were spared the prenatal stressors. But while their daughters grew up as expected, their sons misinterpreted social cues throughout their lives. In adolescence, males born to stress and smog-exposed mothers preferred hanging out with a yellow rubber duck rather than a nearby mouse (mice generally prefer the company of one of their own rather than a bath toy).

Next, Block and her team did what any card-holding neuroscientist would do: They examined whether the brain had been rewired early, leading to more self-conscious adolescent boys. Specifically, the research team wondered if male brains weren’t getting their necessary refinement early in development.

Early in life, all animals are born with an overabundance of brain cell connections, called synapses, which must be reduced as we grow. Synapses leading to successful tasks, like picking up a drink, are maintained and strengthened, while connections that lead to unsuccessful attempts are removed.

Stressed mothers who inhaled diesel fumes gave birth to men who, as toddlers, missed their programmed synaptic shaving in the anterior cingulate cortex (ACC), a brain region important for perceiving and producing social cues. Males’ overabundance of synapses in this region seemed to explain their timid social tendencies in adolescence, but it left open the question of how a double hit of smog and stress during gestation shuts down typical brain sculpting.

To answer this question, Block and his team looked at the immune system, specifically immune cells in the brain called microglia.

Apart from watching for bacteria and viruses, microglia are also on alert for weak or dead synapses, which they easily suck up to help tidy up the brain. Block reasoned that if there were more synapses than usual, there might not be as many microglia in the brains of affected men.

To his surprise, Block found that adolescent males of stressed mothers had as much microglia in the ACC as their peers of unstressed mothers. However, smog and housing stress lead to microglia containing less protein that stimulate their appetite for synapses, which likely explains the observed proliferation.

As an adult, everything changed. Males from mothers exposed to smog and stress 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 Professor of Neurobiology and psychiatrist Kafui Dzirasa, MD. , PhD.

Autistic people are often mistakenly assumed to be less social, but Block said, “If you’ve met an autistic person, then you’ve met an autistic person.

Dzirasa adds that many of his autistic patients would fail the standard lab tests used to diagnose mice, which essentially classify rodents as autistic if they are less likely to socialize. Instead, Dzirasa and Block say that for people with autism, it’s more about misunderstanding social cues and conventions rather than being inherently introverted.

Block and Bilbo suggest that this work provides a clear mechanism in mice that may explain why high levels of air pollution increase a child’s likelihood of developing autism only if born in a poor neighborhood. It could also lead to drugs to help prevent microglia from being manipulated by environmental stressors, as diesel exhaust and housing stress trigger a similar immune response when pregnant women catch the flu.

For now, Bilbo and her team hope that this unequivocal evidence on the impact of stress and air pollution during pregnancy will spur policymakers to promote legislation supporting clean air initiatives and services. social, such as the improvement and expansion of social housing.

“You can’t ignore the mechanistic results of this study,” Bilbo said. “It’s happening, and that’s how it is.”

Research support came from the US National Institutes of Health (R01ES025549, R01MH120158, 1R01EB026937, F32ES029912, F32HD104430), US National Sciences Foundation (DGE 1644868), WM Keck Foundation, Howard Hughes Medical Institute and the Robert and Donna E. Landreth Family Fund, Duke University (Trinity College of Arts & Sciences, a Dean’s Graduate Fellowship through the Graduate School and a Summer Undergraduate Fellowship through the Department of Cell Biology ).

QUOTE: “Prenatal environmental stressors impair postnatal microglia function and adult behavior in males”, Carina L. Block, Oznur Eroglu, Stephen D. Mague, Caroline J. Smith, Alexis M. Ceasrine, Chaichontat Sriworarat , Cameron Blount, Kathleen A. Beben, Karen E. Malacon, Nkemdilim Ndubuizu, Austin Talbot, Neil M. Gallagher, Young Chan Jo, Timothy Nyangacha, David E. Carlson, Kafui Dzirasa, Cagla Eroglu, Staci D. Bilbo. Cell Reports, August 2, 2022. DOI: 10.1016/j.celrep.2022.111161

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