PMID- 37156305 OWN - NLM STAT- MEDLINE DCOM- 20230519 LR - 20230521 IS - 1872-9711 (Electronic) IS - 0161-813X (Linking) VI - 96 DP - 2023 May TI - Locomotion and brain gene expression exhibit sex-specific non-monotonic dose-response to HFPO-DA during Drosophila melanogaster lifespan. PG - 207-221 LID - S0161-813X(23)00065-7 [pii] LID - 10.1016/j.neuro.2023.05.005 [doi] AB - BACKGROUND: Legacy per- and polyfluoroalkyl substances (PFAS), known for their environmental persistence and bio-accumulative properties, have been phased out in the U.S. due to public health concerns. A newer polymerization aid used in the manufacture of some fluoropolymers, hexafluoropropylene oxide-dimer acid (HFPO-DA), has lower reported bioaccumulation and toxicity, but is a potential neurotoxicant implicated in dopaminergic neurodegeneration. OBJECTIVE: We investigated HFPO-DA's bio-accumulative potential and sex-specific effects on lifespan, locomotion, and brain gene expression in fruit flies. METHODS: We quantified bioaccumulation of HFPO-DA in fruit flies exposed to 8.7 x 10(4) microg/L of HFPO-DA in the fly media for 14 days via UHPLC-MS. Long-term effect on lifespan was determined by exposing both sexes to 8.7 x 10(2) - 8.7 x 10(5) microg/L of HFPO-DA in media. Locomotion was measured following 3, 7, and 14 days of exposures at 8.7 x 10(1) - 8.7 x 10(5) microg/L of HFPO-DA in media, and high-throughput 3'-end RNA-sequencing was used to quantify gene expression in fly brains across the same time points. RESULTS: Bioaccumulation of HFPO-DA in fruit flies was not detected. HFPO-DA-induced effects on lifespan, locomotion, and brain gene expression, and lowest adverse effect level (LOAEL) showed sexually dimorphic patterns. Locomotion scores significantly decreased in at least one dose at all time points for females and only at 3-day exposure for males, while brain gene expression exhibited non-monotonic dose-response. Differentially expressed genes correlated to locomotion scores revealed sex-specific numbers of positively and negatively correlated genes per functional category. CONCLUSION: Although HFPO-DA effects on locomotion and survival were significant at doses higher than the US EPA reference dose, the brain transcriptomic profiling reveals sex-specific changes and neurological molecular targets; gene enrichments highlight disproportionately affected categories, including immune response: female-specific co-upregulation suggests potential neuroinflammation. Consistent sex-specific exposure effects necessitate blocking for sex in experimental design during HFPO-DA risk assessment. CI - Copyright (c) 2023 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Vu, Jeanne P AU - Vu JP AD - Boz Life Science Research and Teaching Institute, San Diego, CA, USA; San Diego State University, Graduate School of Public Health, San Diego, CA, USA; University of California, San Diego, Division of Extended Studies, La Jolla, CA, USA. FAU - McLamb, Flannery AU - McLamb F AD - Boz Life Science Research and Teaching Institute, San Diego, CA, USA; University of California, San Diego, Division of Extended Studies, La Jolla, CA, USA. FAU - Feng, Zuying AU - Feng Z AD - Boz Life Science Research and Teaching Institute, San Diego, CA, USA; San Diego State University, Graduate School of Public Health, San Diego, CA, USA. FAU - Griffin, Lindsey AU - Griffin L AD - Boz Life Science Research and Teaching Institute, San Diego, CA, USA; University of California, San Diego, Division of Extended Studies, La Jolla, CA, USA. FAU - Gong, Sylvia AU - Gong S AD - Boz Life Science Research and Teaching Institute, San Diego, CA, USA; San Diego State University, Graduate School of Public Health, San Diego, CA, USA; University of California, San Diego, Division of Extended Studies, La Jolla, CA, USA. FAU - Shea, Damian AU - Shea D AD - Statera Environmental, Raleigh, NC, USA. FAU - Szuch, Mary A AU - Szuch MA AD - Boz Life Science Research and Teaching Institute, San Diego, CA, USA. FAU - Scott, Savannah AU - Scott S AD - Boz Life Science Research and Teaching Institute, San Diego, CA, USA. FAU - Gersberg, Richard M AU - Gersberg RM AD - San Diego State University, Graduate School of Public Health, San Diego, CA, USA. FAU - Bozinovic, Goran AU - Bozinovic G AD - Boz Life Science Research and Teaching Institute, San Diego, CA, USA; San Diego State University, Graduate School of Public Health, San Diego, CA, USA; University of California, San Diego, School of Biological Sciences, La Jolla, CA, USA. Electronic address: gbozinovic@ucsd.edu. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230506 PL - Netherlands TA - Neurotoxicology JT - Neurotoxicology JID - 7905589 RN - 0 (ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate) RN - 0 (Fluorocarbons) SB - IM MH - Male MH - Animals MH - Female MH - *Drosophila melanogaster/genetics MH - Longevity/genetics MH - *Fluorocarbons/toxicity MH - Gene Expression MH - Brain/metabolism MH - Locomotion OTO - NOTNLM OT - Brain OT - Gene expression OT - HFPO-DA OT - Lifespan OT - Locomotion COIS- Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare no competing interests. DS is under contract to provide technical services to Chemours who manufactures HFPO-DA. Chemours had no role in the study design, nor the collection, analysis, and interpretation of data, nor in writing the manuscript. EDAT- 2023/05/09 00:42 MHDA- 2023/05/19 06:42 CRDT- 2023/05/08 19:20 PHST- 2023/02/16 00:00 [received] PHST- 2023/05/04 00:00 [revised] PHST- 2023/05/05 00:00 [accepted] PHST- 2023/05/19 06:42 [medline] PHST- 2023/05/09 00:42 [pubmed] PHST- 2023/05/08 19:20 [entrez] AID - S0161-813X(23)00065-7 [pii] AID - 10.1016/j.neuro.2023.05.005 [doi] PST - ppublish SO - Neurotoxicology. 2023 May;96:207-221. doi: 10.1016/j.neuro.2023.05.005. Epub 2023 May 6.