Perfluorohexanesulfonic Acid (PFHxS) Dysregulates Lipid Homeostasis in Early Life Stage Fish
A frequently detected perfluorinated compound in the environment, perfluorohexanesulfonic acid (PFHxS), can alter lipid metabolism in developing fish. This work identifies a novel mechanism in which PFHxS targets lipid metabolism pathways by using multiple omic techniques and modeling approaches.
What is perfluorohexanesulfonic acid?
PFHxS is a per-and polyfluoroalkyl substance (PFAS) that is commonly produced for waterproofing and stain-protecting coatings for carpets, textiles, electroplating, and food packages. The widespread production of PFHxS has led to an increased presence in the environment and detection in aquatic systems, including being found in drinking water.
Although PFHxS was listed in the Stockholm Convention in 2022 and banned for use, this compound is capable of being formed secondarily from the treatment of drinking water with chlorine and ammonia, a process referred to as chloramination. PFHxS has been reported to bioaccumulate in organisms and cause dysregulations in lipid metabolism, although the effects of PFHxS to aquatic species at environmentally relevant concentrations are not well understood.
Study setup
To better understand the potential toxic effects of PFHxS to early life stage fish, zebrafish (Danio rerio) were exposed to concentrations of PFHxS detected in the environment. The toxic mechanism in which PFHxS acts through was characterized, with a focus on the peroxisome proliferator-activated receptor (PPAR) signaling pathway, as lipid homeostasis can be dysregulated following exposure to perfluorinated compounds.
Embryonic zebrafish were exposed to PFHxS for five days at environmentally relevant exposure concentrations. The accumulation of PFHxS in zebrafish was measured, a molecular docking assessment was used to look at the capacity of PFHxS to bind to specific PPAR receptors, and the lipidome and transcriptome were profiled, which consists of identifying lipids and genes that are altered following exposure, respectively. These two omic profiles, lipidome and transcriptome, were integrated to better predict biological pathways that are impaired in zebrafish larvae when exposed to PFHxS. To link molecular level effects and molecular docking endpoints, higher biological endpoints were assessed, including morphological measurements and swimming behavior.
Generalized results
The lipidomic profile of larval zebrafish was altered following PFHxS exposure, which had not been characterized before. Endogenous lipids were among the most impacted by PFHxS, inducing lipid metabolism remodeling, dysregulating lipid homeostasis. Similarly, transcriptomic profiles demonstrated lipid disorders were related to fatty acid metabolism, synthesis of lipids, as well as the uptake of lipids, altering the expression of lipid metabolism genes. When both omic profiles were integrated it was determined that the PPAR signaling pathway was a predominant target of PFHxS in inducing lipid metabolism effects.
Molecular docking simulations found that PPARα was responsible for mediating lipid dysregulation through the binding of PFHxS to the active site of PPARα, suggesting that PFHxS activates PPARα upon binding. Interestingly, PFHxS-exposed zebrafish didn’t have an altered body length, weight, or swimming behavior when compared to untreated zebrafish, likely due to an acute exposure. This work suggests that the integration of omics can be a useful tool for the evaluation of PFAS to fish development while offering a new insight for applications in environmental risk assessments as sensitive endpoints of environmental contaminants. The major takeaway is that PFHxS induces lipid dysregulation in zebrafish by acting through the activation of PPARα, which is likely a key molecular initiating event.
There is still much to learn on this topic
The frequent detection of PFHxS in the aquatic environment and capacity to be transported up the food web raises concern for wildlife and fish. The findings in this study identify a mechanism in which PFHxS can cause harm in early life stage fish. However, the effect of PFHxS to other aquatic or terrestrial species is not fully understood, nor the difference in toxic response between short and long-term exposures.
Further research is needed to better determine how these effects may translate to different developmental stages, different species, and under different exposure concentrations of PFHxS. This data can be used to further mitigate toxic effects of compounds similar to PFHxS and other forever chemicals to help better manage natural resources.
A frequently detected perfluorinated compound in the environment, perfluorohexanesulfonic acid (PFHxS), can alter lipid metabolism in developing fish. This work identifies a novel mechanism in which PFHxS targets lipid metabolism pathways by using multiple omic techniques and modeling approaches.
What is perfluorohexanesulfonic acid?
PFHxS is a per-and polyfluoroalkyl substance (PFAS) that is commonly produced for waterproofing and stain-protecting coatings for carpets, textiles, electroplating, and food packages. The widespread production of PFHxS has led to an increased presence in the environment and detection in aquatic systems, including being found in drinking water.
Although PFHxS was listed in the Stockholm Convention in 2022 and banned for use, this compound is capable of being formed secondarily from the treatment of drinking water with chlorine and ammonia, a process referred to as chloramination. PFHxS has been reported to bioaccumulate in organisms and cause dysregulations in lipid metabolism, although the effects of PFHxS to aquatic species at environmentally relevant concentrations are not well understood.
Study setup
To better understand the potential toxic effects of PFHxS to early life stage fish, zebrafish (Danio rerio) were exposed to concentrations of PFHxS detected in the environment. The toxic mechanism in which PFHxS acts through was characterized, with a focus on the peroxisome proliferator-activated receptor (PPAR) signaling pathway, as lipid homeostasis can be dysregulated following exposure to perfluorinated compounds.
Embryonic zebrafish were exposed to PFHxS for five days at environmentally relevant exposure concentrations. The accumulation of PFHxS in zebrafish was measured, a molecular docking assessment was used to look at the capacity of PFHxS to bind to specific PPAR receptors, and the lipidome and transcriptome were profiled, which consists of identifying lipids and genes that are altered following exposure, respectively. These two omic profiles, lipidome and transcriptome, were integrated to better predict biological pathways that are impaired in zebrafish larvae when exposed to PFHxS. To link molecular level effects and molecular docking endpoints, higher biological endpoints were assessed, including morphological measurements and swimming behavior.
Generalized results
The lipidomic profile of larval zebrafish was altered following PFHxS exposure, which had not been characterized before. Endogenous lipids were among the most impacted by PFHxS, inducing lipid metabolism remodeling, dysregulating lipid homeostasis. Similarly, transcriptomic profiles demonstrated lipid disorders were related to fatty acid metabolism, synthesis of lipids, as well as the uptake of lipids, altering the expression of lipid metabolism genes. When both omic profiles were integrated it was determined that the PPAR signaling pathway was a predominant target of PFHxS in inducing lipid metabolism effects.
Molecular docking simulations found that PPARα was responsible for mediating lipid dysregulation through the binding of PFHxS to the active site of PPARα, suggesting that PFHxS activates PPARα upon binding. Interestingly, PFHxS-exposed zebrafish didn’t have an altered body length, weight, or swimming behavior when compared to untreated zebrafish, likely due to an acute exposure. This work suggests that the integration of omics can be a useful tool for the evaluation of PFAS to fish development while offering a new insight for applications in environmental risk assessments as sensitive endpoints of environmental contaminants. The major takeaway is that PFHxS induces lipid dysregulation in zebrafish by acting through the activation of PPARα, which is likely a key molecular initiating event.
There is still much to learn on this topic
The frequent detection of PFHxS in the aquatic environment and capacity to be transported up the food web raises concern for wildlife and fish. The findings in this study identify a mechanism in which PFHxS can cause harm in early life stage fish. However, the effect of PFHxS to other aquatic or terrestrial species is not fully understood, nor the difference in toxic response between short and long-term exposures.
Further research is needed to better determine how these effects may translate to different developmental stages, different species, and under different exposure concentrations of PFHxS. This data can be used to further mitigate toxic effects of compounds similar to PFHxS and other forever chemicals to help better manage natural resources.