Evaluation of Developmental Toxicity, Developmental Neurotoxicity, and Tissue Dose in Zebrafish Exposed to GenX and Other PFAS

Abstract

BACKGROUND: Per-and polyfluoroalkyl substances (PFAS) are a diverse class of industrial chemicals with widespread environmental occurrence. Exposure to long-chain PFAS is associated with developmental toxicity, prompting their replacement with short-chain and fluoroether compounds. There is growing public concern over the safety of replacement PFAS. OBJECTIVE: We aimed to group PFAS based on shared toxicity phenotypes. METHODS: Zebrafish were developmentally exposed to 4,8-dioxa-3H-perfluorononanoate (ADONA), perfluoro-2-propoxypropanoic acid (GenX Free Acid), perfluoro-3,6-dioxa-4-methyl-7-octene-1-sulfonic acid (PFESA1), perfluorohexanesulfonic acid (PFHxS), perfluorohexanoic acid (PFHxA), perfluoro-n-octanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), or 0.4% dimethyl sulfoxide (DMSO) daily from 0-5 d post fertilization (dpf). At 6 dpf, developmental toxicity and developmental neurotoxicity assays were performed, and targeted analytical chemistry was used to measure media and tissue doses. To test whether aliphatic sulfonic acid PFAS cause the same toxicity phenotypes, perfluorobutanesulfonic acid (PFBS; 4-carbon), perfluoropentanesulfonic acid (PFPeS; 5-carbon), PFHxS (6-carbon), perfluoroheptanesulfonic acid (PFHpS; 7-carbon), and PFOS (8-carbon) were evaluated. RESULTS: PFHxS or PFOS exposure caused failed swim bladder inflation, abnormal ventroflexion of the tail, and hyperactivity at nonteratogenic concentrations. Exposure to PFHxA resulted in a unique hyperactivity signature. ADONA, PFESA1, or PFOA exposure resulted in detectable levels of parent compound in larval tissue but yielded negative toxicity results. GenX was unstable in DMSO, but stable and negative for toxicity when diluted in deionized water. Exposure to PFPeS, PFHxS, PFHpS, or PFOS resulted in a shared toxicity phenotype characterized by body axis and swim bladder defects and hyperactivity. CONCLUSIONS: All emerging fluoroether PFAS tested were negative for evaluated outcomes. Two unique toxicity signatures were identified arising from structurally dissimilar PFAS. Among sulfonic acid aliphatic PFAS, chemical potencies were correlated with increasing carbon chain length for developmental neurotoxicity, but not developmental toxicity. This study identified relationships between chemical structures and in vivo phenotypes that may arise from shared mechanisms of PFAS toxicity. These data suggest that developmental neurotoxicity is an important end point to consider for this class of widely occurring environmental chemicals.

An assessment of serum‐dependent impacts on intracellular accumulation and genomic response of per‐ and polyfluoroalkyl substances in a placental trophoblast model

“…Control media also contained 0.1% methanol. Dimethyl sulfoxide (DMSO) was not utilized for tissue culture since DMSO has been found to degrade the ether portion of HFPO‐DA in solution 28,29 …”

“…Dimethyl sulfoxide (DMSO) was not utilized for tissue culture since DMSO has been found to degrade the ether portion of HFPO-DA in solution. 28,29 The JEG3 cell line, trophoblast lineage derived from a human placental choriocarcinoma, was acquired from ATCC (HTB-36; Manassas, VA) and cultured in serum-supplemented media (SSM) and serum-free media (SFM) as detailed in Supplemental Table S2. In brief, SSM media Island, NY).…”

Per- and Polyfluoroalkyl Substances (PFAS) Neurotoxicity in Sentinel and Non-Traditional Laboratory Model Systems: Potential Utility in Predicting Adverse Outcomes in Human Health

“…Interestingly, PFOS, PFOA, and PFNA all increased the distance swam in the dark after exposure through 120 hpf followed by 2 weeks of depuration (Table 2) [47]. The hyperactivity after PFOS exposure was corroborated in a study where D. rerio exposed through 6 dpf had significantly increased movement, but exposure to PFOA did not affect movement [57]. Furthermore, 89 µM perfluoroheptanoate (PFHpA) also increased the swimming distance in the light cycle after exposure through 144 hpf (Table 3) [58].…”

“…Furthermore, 89 µM perfluoroheptanoate (PFHpA) also increased the swimming distance in the light cycle after exposure through 144 hpf (Table 3) [58]. Both PFHxS and PFHxA caused increased activity along with perfluoropentane sulfonate (PFPeS) and PFHpS [57]. However, the PFAS 1H-indole-2-sulfonic acid, 5-((aminocarbonyl)hydrazono)-2,3,5,6-tetrahydro-1-methyl-6-oxo salt (ADONA), PFBS, and perfluoro-3,6-dioxa-4-methyl-7-octene-1-sulfonate (PFESA1) did not have any effects on behavior [57].…”

“…Both PFHxS and PFHxA caused increased activity along with perfluoropentane sulfonate (PFPeS) and PFHpS [57]. However, the PFAS 1H-indole-2-sulfonic acid, 5-((aminocarbonyl)hydrazono)-2,3,5,6-tetrahydro-1-methyl-6-oxo salt (ADONA), PFBS, and perfluoro-3,6-dioxa-4-methyl-7-octene-1-sulfonate (PFESA1) did not have any effects on behavior [57]. These data on swimming speed and distance indicate that various PFAS could be affecting various systems, such as motor or anxiety, which should be studied in other models as a potential effect of PFAS exposure.…”