Pollution and stress alter brain development and social behavior in male mice

The results of a newly reported study on mice by scientists at Duke University support marine oceanographer Carina Block’s idea that the jet exhaust to which she and her female sailors were regularly exposed, coupled with unavoidable work stress, led to adverse health outcomes for their children. children. The study results indicate that, in addition to unsafe homes during pregnancy, air pollution leads to autism-like social behavior and altered brain wiring in male, but not female, puppies. The results also suggest that the immune system is to blame for developing these neurodevelopmental disorders (NDDs).

“I was pregnant, stressed and working near airplanes,” Block recalls. “I walked past the jet fuel outlet every day. And my child ended up with a neurodevelopmental disorder called hydrocephalus.” While Block’s daughter is now doing well, the study by Block and colleagues, published in Mobile Reports, provides evidence that if Block had had a son, he might have been born with autism. Block, along 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 entitled, “Prenatal Environmental Stressors Affect Postnatal Microglia Function and adult behavior in men.” In the study, the team concluded, “…our findings provide an important first step toward revealing the non-genetic causes for NDDs so that preventive and therapeutic approaches can be developed along with informed policy changes.”

Air pollution, such as exhaust fumes emitted by diesel engines in trucks, has been linked to increased rates of neurodevelopmental disorders such as: schizophrenia and autism, the authors noted. “The incidence of neurodevelopmental disorders (NDDs) has increased in recent decades, suggesting a role for environmental non-genetic factors,” they wrote in their paper. “In addition, sex is a major risk factor for these conditions, with a strong male bias. Exposure to air pollutants 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 around the world live alone in cities with unhealthy air one in 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 others and it is 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 rich people aren’t stressed,” Bilbo said. “But it’s different if you have to worry about where you’re going to live and whether you’re safe in your home.”

While there exist data in humans In support of Bilbo’s claim, it is impossible and unethical to test these ideas directly in pregnant women in order to identify biological mechanisms through which air pollution and stress can combine to rewire the brains of developing children. Block and her team instead exposed pregnant mice to the poor housing and air quality that many people endure every day, and watched their offspring fare.

As a proxy for air pollution, the mouse mothers were exposed to diesel exhaust particles. As an added stressor, towards the end of their pregnancies, the female mice were allocated less building materials than usual to build nests for their pups, effectively representing insufficient housing.

The study results confirmed that the stressed mothers continued to be excellent parents, in that they cared for and nurtured their pups just as well as the mouse mothers who were spared prenatal stressors. However, while the female pups of stressed and contaminant-exposed mothers grew up as expected, the male pups understood social cues throughout life. In one set of experiments, it was shown that as teenagers, these males preferred to interact with a yellow rubber duck than with a nearby mouse (mice usually prefer the company of their own rather than a bath toy ).

Block and her team then examined whether the male pups’ brains had been rewired early on, leading to shy male teens. In particular, the research team wondered whether the male brain was not given the necessary sophistication early on in development.

Early in life, all animals are born with an abundance of brain cell synapses, which are reduced as the animal grows. The synapses that lead to successful tasks, such as picking up a glass, are preserved and strengthened, while the connections that lead to failed attempts are removed. “In early postnatal brain development, an exuberant period of synaptogenesis is closely followed and overlaps with a period of synaptic pruning, eliminating weak or unnecessary synapses,” the scientists said.

The team’s studies showed that stressed mothers who inhaled diesel fumes gave birth to male pups who, as toddlers, appeared to lack this synaptic organization in the anterior cingulate cortex (ACC), a brain region important for perceiving and producing social cues. An abundance of synapses in this area of ​​the male pups’ brains seemed to explain their shy social tendencies as teens, but this also left open the question of how the smog and stress during pregnancy stopped the typical brain sculpting.

To investigate this further, Block and her team looked at the immune system, specifically immune cells in the brain called microglia. Microglia check for bacteria and viruses, but they’re also on the lookout for weak or dead synapses, which they easily remove to clean up the brain. “Microglia are the brain’s primary immunocompetent cells and are extremely sensitive to homeostasis disturbances and thus may be poised to act in an immediate response to environmental insults,” the team noted. “Microglia are also essential regulators of activity-dependent synaptic remodeling during development, pruning inappropriate/weak synapses while sparing suitable/strong connections.”

Block reasoned that if there were more synapses than normal in the brains of male pups from stressed and pollution-exposed mothers, there might not be as many microglia in the brains of affected males either. In fact, the team noted, “…we and others have found sex differences in microglial development, maturation and function, including increased relative expression of microglial genes in male brains, compared to females. Interestingly, the microglial genes enriched in male brains are also involved in ASD.”

But surprisingly, Block and colleagues found that adolescent males from stressed mothers had just as many microglia in the ACC as their peers from unstressed mothers. But smog and housing stress were associated with microglia having less of the protein that stimulates their appetite for synapses, and this could likely explain the abundance of synapses.

Interestingly enough, the situation seemed to reverse in adulthood. Male mice born to smog and stress-exposed mothers now had fewer synapses in their ACC and were more sociable than their unexposed peers. This atypical tendency to be more outgoing rather than reserved reflected the behavior and brain activity of mice with autism-related 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 believed to be less sociable, but Block shared that, “If you’ve met one person with autism, 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 consider rodents to have autism if they are less likely to socialize. Instead, Dzirasa and Block say that for people with autism, it’s more of a misunderstanding of social cues and conventions than they are inherently introverted.

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

For now, Bilbo and her team hope their newly reported evidence on the impact of stress and air pollution during pregnancy could prompt policymakers to promote legislation to support clean air initiatives and social services, such as improved and expanded public housing. “You can’t ignore the mechanistic findings of this study,” Bilbo said. “This is happening, and this is how.”

The authors acknowledge the limitations of their study and conclude: “Our findings elucidate a mechanism by which environmental pollutants may synergize with psychosocial stress in pregnant mothers and cause MIA, which has specific long-term effects on male brain development and function. In particular, this is alarming, now more than ever, as ongoing climate change resulting from increased economic activity and reduced environmental protection enforcement has led to a rapid deterioration in air quality in recent years.Increased air pollution is likely to synergize with social stressors in vulnerable populations, causing further differences in the well-being of future generations.”

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