PFAS Chemicals Impair Brain Development

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Some perfluoroalkyl substances (PFAS) are difficult to break down and are also known as “forever chemicals”. They have adverse health effects and can cause liver damage, obesity, hormonal disorders and cancer. A research team from the Helmholtz Center for Environmental Research (UFZ) has investigated the effects of PFAS on the brain. Combining the latest molecular biology methods with the zebrafish model, the researchers uncovered the mechanism of action and identified the relevant genes. These genes are also present in humans. The test procedure developed at UFZ can also be used for risk assessment of other neurotoxic chemicals. The study was recently published in Environmental health perspective.

PFAS are used in many everyday products (cosmetics, outdoor clothing, coated cookware, etc.) due to their properties such as heat resistance, water repellency, oil repellency and high durability. But it is precisely these properties that make PFAS so problematic. “Some PFAS are chemically stable, so they accumulate in the environment and enter the body via air, drinking water and food,” says UFZ toxicologist Professor Tamara Tal. This group of substances, produced since the 1950s and now including thousands of different compounds, is almost impossible to avoid even with careful intake. “Research is greatly needed, especially when it comes to developing rapid, reliable and cost-effective test systems to assess the risk of exposure to PFAS,” says Professor Tal. So far, it has been difficult to assess the environmental and health impacts.

In this study, the researchers investigated how exposure to PFASs affects brain development. They used a zebrafish model, which is commonly used in toxicology studies. One advantage of this model is that about 70% of the genes found in zebrafish show how PFASs affect brain development (Danio Lelio) are also present in humans. Therefore, the findings from the zebrafish model may also be applicable to humans. In their experiments, the researchers exposed zebrafish to two structurally similar members of the PFAS group (PFOS and PFHxS). They then used molecular biology and bioinformatics methods to investigate which genes were disrupted in the brains of PFAS-exposed fish larvae compared to unexposed control fish. “In PFAS-exposed zebrafish, the peroxisome proliferator-activated receptor (ppar) gene family, which is also present in slightly altered form in humans, was particularly active,” says Sebastian Gutzfeld, a doctoral student at UFZ and lead author of the study. “Toxicity studies have shown that this is the case as a result of exposure to PFAS, albeit in the liver. Now we have been able to demonstrate this for the brain as well.”

But how do changes in ppar gene activity caused by PFAS exposure affect the brain development and behavior of zebrafish larvae? The researchers investigated this in further studies using the zebrafish model. They used the CRISPR/Cas9 technique, also known as genetic scissors. “Using genetic scissors, we were able to selectively cut individual ppar genes or multiple ppar genes so that they do not function normally,” explains Gutsfeld. “We wanted to determine which ppar genes were directly related to the changes in larval behavior caused by PFAS exposure.” Evidence of the underlying mechanism was provided directly. In contrast to unaltered zebrafish, knockdown fish using genetic scissors should not show any behavioral changes after PFAS exposure.

Two behavioral endpoints

In one set of experiments, the researchers exposed zebrafish to PFOS or PFHxS continuously during early developmental stages from days 1 to 4, and in another set of experiments, they exposed them only on day 5. On day 5, the researchers observed swimming behavior. To this end, they used two different behavioral endpoints. The first endpoint measured swimming activity during an extended dark period. Fish exposed to PFAS swam more than fish not exposed to PFAS, regardless of whether they were exposed to PFAS continuously during brain development or just before behavioral testing. Interestingly, the hyperactivity was only present when the chemicals were in the environment. When the researchers removed PFOS or PFHxS, the hyperactivity subsided. The second endpoint measured the startle response after a dark stimulus. “We observed hyperactive swimming behavior in response to the stimulus in zebrafish exposed to PFOS for four days,” says Gutsfeld. In contrast, zebrafish exposed only to PFOS or PFHxS on day 5 did not exhibit a hypersensitive startle response.

Based on these responses, the researchers conclude that exposure to PFOS is associated with abnormal outcomes, especially during sensitive developmental stages of the brain. Using knockdown zebrafish, the researchers identified two genes from the ppar group that mediate PFOS-induced behaviors.

“These genes are also present in humans, so it is possible that PFAS may have similar effects in humans,” Tal concludes. Tal and his collaborating scientists hope to investigate the neuroactive effects of other PFAS in future research projects and to extend this method so that it can eventually be used to assess the risks of environmental chemicals, including PFAS.

reference: Gutsfeld S, Wehmas L, Omoyeni I, et al. Investigation of peroxisome proliferator-activated receptor genes required for visual startle hyperactivity in zebrafish larvae exposed to structurally similar per- and polyfluoroalkyl compounds (PFAS). Environmental Health Perspective2024;132(7):077007. doi: 10.1289/EHP13667

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