Developmental Toxicity of Photolithography-Relevant Per- and Polyfluoroalkyl Substances (PFAS) Reveals Concerns for Less-Studied Functional Groups

Per- and polyfluoroalkyl substances (PFAS) are used throughout semiconductor manufacturing, including photolithography, yet many remain toxicologically uncharacterized. This study used the zebrafish embryo assay to assess developmental toxicity and gene expression changes (<i>fgf10a</i>, <i>igf1</i>, <i>fabp10a</i>, <i>pparg</i>, and <i>mttp</i>) linked to growth and lipid metabolism for nine legacy and emerging photolithography-relevant PFAS. Exposure induced increased lethality and common malformations, including failure of swim bladder inflation and yolk sac edema. Transcriptional analysis revealed that certain PFAS, especially triphenylsulfonium perfluoro-1-butanesulfonate, 1H,1H,2H,2H-perfluorooctane sulfonic acid, perfluorooctanoic acid, and bis(1,1,2,2,3,3,4,4,4-nonafluoro-1-butanesulfonyl)imid, significantly downregulated <i>pparg</i> and <i>mttp</i> expression, even at environmentally relevant concentrations. Our findings raise concerns that certain PFAS actively used in photolithography, including some with less-studied functional groups (e.g., perfluoroalkyl dicarboxylic acids and perfluorosulfonamides), are more toxic than equivalent-chain monocarboxylic acid and legacy PFAS, respectively, providing mechanistic insight into PFAS-induced toxicity. These results help inform the selection of safer chemicals in semiconductor manufacturing.