Structure-specific variation in per- and polyfluoroalkyl substances toxicity among genetically diverseCaenorhabditis elegansstrains

Abstract

AbstractBackgroundThere are >14,500 structurally diverse per- and polyfluoroalkyl substances (PFAS). Despite knowledge that these “forever chemicals” are in 99% of humans, mechanisms of toxicity and adverse health effects are incompletely known. Furthermore, the contribution of genetic variation to PFAS susceptibility and health consequences is unknown.ObjectivesWe determined the toxicity of a structurally distinct set of PFAS in twelve genetically diverse strains of the genetic model systemCaenorhabditis elegans.MethodsDose-response curves for four perfluoroalkyl carboxylic acids (PFNA, PFOA, PFPeA, and PFBA), two perfluoroalkyl sulfonic acids (PFOS and PFBS), two perfluoroalkyl sulfonamides (PFOSA and PFBSA), two fluoroether carboxylic acids (GenX and PFMOAA), one fluoroether sulfonic acid (PFEESA), and two fluorotelomers (6:2 FCA and 6:2 FTS) were determined in theC. eleganslaboratory reference strain, N2, and eleven genetically diverse wild strains. Body length was quantified by image analysis at each dose after 48 hr of developmental exposure of L1 arrest-synchronized larvae to estimate effective concentration values (EC50).ResultsThere was a significant range in toxicity among PFAS: PFOSA > PFBSA ≈ PFOS ≈ PFNA > PFOA > GenX ≈ PFEESA > PFBS ≈ PFPeA ≈ PFBA. Long-chain PFAS had greater toxicity than short-chain, and fluorosulfonamides were more toxic than carboxylic and sulfonic acids. Genetic variation explained variation in susceptibility to PFBSA, PFOS, PFBA, PFOA, GenX, PFEESA, PFPeA, and PFBA. There was significant variation in toxicity amongC. elegansstrains due to chain length, functional group, and between legacy and emerging PFAS.ConclusionC. elegansrespond to legacy and emerging PFAS of diverse structures, and this depends on specific structures and genetic variation. Harnessing the natural genetic diversity ofC. elegansand the structural complexity of PFAS is a powerful New Approach Methodology (NAM) to investigate structure-activity relationships and mechanisms of toxicity which may inform regulation of other PFAS to improve human and environmental health.