8:8 Perfluoroalkyl phosphinic acid affects neurobehavioral development, thyroid disruption, and DNA methylation in developing zebrafish.

Recent studies have reported potential neurotoxicity and epigenetic alteration associated with exposure to several per- and polyfluoroalkyl substances (PFASs). However, such information is limited to a few compounds (e.g., perfluorooctane sulfonate), primarily based on rodent experiments, and the underlying toxicological mechanism(s) for many PFAS in the environment remain poorly understood. In the present study, we investigated 8:8 perfluoroalkyl phosphinic acid (8:8 PFPiA), an under-studied PFAS with high persistency in the environment and biota, using the zebrafish model. We exposed zebrafish embryos (<4 hpf) to various concentrations of 8:8 PFPiA (0, 0.0116, 0.112, 0.343, 1.34, 5.79 μM) for 144 h. Although there was no significant change in survival, hatchability and malformations, zebrafish locomotor speed at 120 h significantly decreased in dark photoperiod. At 144 h, several genes related to thyroid hormones that are essential for neurodevelopment, including corticotropin releasing hormone b (crhb), iodothyronine deiodinase 3a (dio3a), thyroid-stimulating hormone receptor (tshr) and nkx2 homeobox1 (nkx 2.1), were up-regulated by 8:8 PFPiA at 5.79 μM. 8:8 PFPiA also significantly down-regulated a neurodevelopmental gene, elav like neuron-specific RNA binding protein (elavl3), at 1.34 and 5.79 μM; in addition, one oxidative stress gene was slightly but significantly up-regulated. Further, global DNA methylation was significantly decreased at higher treatment levels, identifying effects of 8:8 PFPiA on epigenetic regulation. However, promoter DNA methylation of selected genes (dio3, tshr, nkx2.1) were not statistically altered, though dio3 methylation showed a decreasing trend with 8:8 PFPiA exposure. Our results specifically advance an understanding of molecular toxicology of PFPiA and more broadly present an approach to define diverse responses during animal alternative assessments of PFASs. Unlabelled Image • Early exposure to 8:8 PFPiA reduced swimming activity in zebrafish. • Increased thyroid related genes and decreased neurodevelopmental genes were observed. • 8:8 PFPiA decreased methylation of global DNA or the DIO3 gene. • Up-regulation of oxidative stress gene may be related to decreased DNA methylation. • Future mechanistic toxicology research with understudied PFAS is warranted. [ABSTRACT FROM AUTHOR]