Early exposure to forever chemicals linked to altered brain genes and impulsive behavior in rats

A study on rats found that exposure to perfluorooctanesulfonic acid (PFOS) altered gene expression in the nucleus accumbens, hippocampus, and prefrontal cortex regions of the brain of their offspring. In turn, this may have led to impaired cognitive performance and more impulsive decision-making. The paper was published in Ecotoxicology and Environmental Safety.

Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals widely used in industrial processes and consumer products due to their resistance to heat, water, and oil. One of these chemicals is perfluorooctanesulfonic acid, or PFOS, a legacy substance that was used for decades in products such as firefighting foams and stain-resistant coatings, as well as in certain manufacturing processes. It is often called a “forever chemical” because it breaks down extremely slowly and can remain in the environment for a very long time.

Although the use of PFOS was largely discontinued in the early years of the 21st century, PFOS remains widely present in both the environment and the human body. PFOS resists metabolic breakdown, resulting in prolonged accumulation in the body. Although the overall levels of PFAS in the environment have declined in recent years, PFOS continues to be the most frequently detected PFAS in human blood. Humans are primarily exposed to PFOS through contaminated water, food, dust, and consumer products.

Studies have indicated that PFOS exposure has adverse effects on the human body, including changes to cholesterol levels, liver-related measures, immune responses, and some pregnancy-related outcomes. Because of these concerns, PFOS production and use have been heavily restricted or phased out in many places around the world.

Study author Shiwen Li and colleagues wanted to explore how prenatal PFOS exposure affects gene expression in three key regions of the brain: the nucleus accumbens, the hippocampus, and the prefrontal cortex. These three regions were chosen because the nucleus accumbens is central to motivation and action, the hippocampus is critical for learning and memory, and the prefrontal cortex is essential for executive function and working memory. The authors also wanted to know whether any changes in gene expression in these three areas are associated with changes in behavior in the PFOS-exposed rats.

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The study was conducted on Long-Evans rats. Pregnant female rats were involved in the study starting from day 12 of embryonic development and delivered their pups naturally. The rats had free access to food and water.

The pregnant female rats were divided into two groups of six. One group was exposed to PFOS through drinking water that contained 15mg of PFOS per liter alongside a small amount of Tween 20 (a chemical used as a mixing agent). The control group drank water with Tween 20 only and no PFOS. The exposure started on the 12th day of the rats’ pregnancies and continued until weaning, which occurred 21 days after the rat pups were born.

Once the offspring reached adulthood, they completed a series of behavioral tests, including an extradimensional set-shifting task (switching from a direction cue to a visual cue) and a delay discounting task. After these tests, the study authors conducted RNA sequencing on the brain tissues of the adult male rats and analyzed gene expression in the three focal brain regions.

The results showed that there were 62 genes with differential expression in the nucleus accumbens tissues of the rats exposed to PFOS. The number of differentially expressed genes in the hippocampus was 34, and there were 59 differentially expressed genes in the prefrontal cortex. Differential expression of genes means that those genes were more or less active in the PFOS-exposed group compared to the control group. These alterations can change how the affected cells function, respond, and develop.

Specifically, the researchers observed changes to genes involved in extracellular matrix interaction—the structural support system of the brain—within the nucleus accumbens. In the prefrontal cortex, PFOS exposure disrupted genes responsible for glutathione metabolism, a critical biological pathway the brain uses to clear out harmful oxidative stress and toxins.

Statistical analyses showed that the differential expression of some of these genes might be mediating the link between PFOS exposure and the outcomes of the behavioral tests. While the rats did not show significant impairments in cognitive flexibility, the results indicated that specific gene alterations were strongly associated with more impulsive decision-making. For example, the PFOS-exposed rats showed a lower preference for a large, delayed reward compared to a small, immediate one, and they gave up more frequently as wait times increased.

“Developmental PFOS exposure may alter gene expression in the nucleus accumbens and prefrontal cortex and was associated with impaired cognitive flexibility and impulsive decision-making,” the study authors concluded in their abstract.

The study contributes to the scientific understanding of the effects of PFOS on the developing nervous system. However, it should be noted that this study was conducted on rats, not on humans. While rats and humans share many physiological similarities, they are still different species, and results in humans may differ. Additionally, the study used a single dosage of the chemical, so it remains unclear how higher or lower environmental doses might alter the severity of the outcomes.

The paper, “Developmental perfluorooctane sulfonate (PFOS) exposure alters gene expression in nucleus accumbens and prefrontal cortex and impairs cognition in rats: A transcriptomic and mediation analysis,” was authored by Shiwen Li, Hongxu Wang, Ana C. Maretti-Mira, Tomas K. D. Manea, Shaun Y. Kim, Lida Chatzi, Jesse A. Goodrich, Tanya L. Alderete, Nathan Young, Ruth I. Wood, and Max T. Aung.