A new study on mice explores how prenatal exposure to an industrial byproduct changes the properties and functions of an important class of cells in the brain called microglia that provide immunological support for neurons and control responses to environmental toxins.

The findings show exposure to TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) in utero could lead to deficits in the brain’s immune system later in life, compromise neural networks and result in neurodevelopmental disorders such as autism spectrum disorders (ASD) and attention deficit hyperactive disorder (ADHD).

The researchers also found pharmacological manipulations later in life can renew microglial populations in the brain, restoring normal microglial function.

The study was published in an article in the journal Brain, Behavior, and Immunity on February 11, 2022, titled “Gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin primes cortical microglia to tissue injury.”

TCDD makes its way into the ambient environment mostly through vehicle exhaust and burning wood. It is found in air, soil, and food, at low levels. The most common route of exposure for humans is through meat, dairy, and fish.

The investigators exposed male mice in utero to TCDD and showed that this led to inflammation which causes microglia to respond abnormally to injury. Using gene expression studies, histology, and two-photon in vivo imaging, the researchers show how TCDD, which binds to a high affinity aryl hydrocarbon receptor on microglia for extended periods changes the cells’ function.

While the microglia appeared healthy—their density, distribution, morphology, and movement were unchanged—using whole cortical RT-qPCR and RNA-sequencing of isolated microglia, the authors show TCDD exposure resulted in subtle, but long-term changes in the transcriptome. This led microglia to become overactivated when responding to focal tissue injury. Microglial overactivation may result in inflammation and damages to neural networks.

To dampen the excessive activation of microglia following injury, the researchers used the drug Pexidartnib and found this led to the replacement of hyperactive microglia with new, normal ones.

Rebecca Lowery, PhD, assistant research professor in the Del Monte Institute for Neuroscience at the University of Rochester, and co-first author of the study, said, “Defects in microglia function resulting from prenatal exposures can be reversed later in life, indicating a possible additional therapeutic avenue for neurodevelopmental disorders.”

The study indicates a developmental time window of susceptibility to TCDD. Prior research had shown TCDD exposure in adults did not result in brain inflammation and did not affect microglia function.

“Microglia are outside of the brain during pregnancy,” said Ania Majewska, PhD, first author on this study. “But after birth they are protected, possibly by the blood brain barrier. This barrier may be what prevents the harmful effects of TCDD from entering the brain.”

In further studies, the team is exploring other environmental toxins that result in long-term microglial dysfunction and changes in neural circuitry.

This study was financially supported by grants from the National Institute of Neurological Diseases and Stroke (NINDS), National Institute of Alcohol abuse and Alcoholism (NIAAA),  National Institute of Environmental Health Sciences (NIEHS), National Institute of General Medical Sciences (NIGMS) and the National Institute of Child Health and Human Development (NICHD).