Treffer: A systems toxicology approach implicates post-transcriptional regulatory networks in reproductive defects from PFAS exposure.
Title:
A systems toxicology approach implicates post-transcriptional regulatory networks in reproductive defects from PFAS exposure.
Authors:
Bline AP; Molecular Toxicology Interdepartmental Program, UCLA, Los Angeles, CA 90095, United States., Jiang H; Institute for Society & Genetics, UCLA, Los Angeles, CA 90095, United States., Levenson M; Molecular Toxicology Interdepartmental Program, UCLA, Los Angeles, CA 90095, United States., Allard P; Molecular Toxicology Interdepartmental Program, UCLA, Los Angeles, CA 90095, United States.; Institute for Society & Genetics, UCLA, Los Angeles, CA 90095, United States.; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, United States.
Source:
Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2025 Nov 01; Vol. 208 (1), pp. 61-81.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Oxford University Press Country of Publication: United States NLM ID: 9805461 Publication Model: Print Cited Medium: Internet ISSN: 1096-0929 (Electronic) Linking ISSN: 10960929 NLM ISO Abbreviation: Toxicol Sci Subsets: MEDLINE
Imprint Name(s):
Publication: 1999- : Cary, NC : Oxford University Press
Original Publication: Orlando, FL : Academic Press, c1998-
Original Publication: Orlando, FL : Academic Press, c1998-
MeSH Terms:
Fluorocarbons*/toxicity , Caenorhabditis elegans*/drug effects , Caenorhabditis elegans*/genetics , Alkanesulfonic Acids*/toxicity , Reproduction*/drug effects , Reproduction*/genetics , Gene Regulatory Networks*/drug effects , Environmental Pollutants*/toxicity, Animals ; Germ Cells/drug effects ; Apoptosis/drug effects
References:
Ecotoxicol Environ Saf. 2018 Aug 30;158:223-229. (PMID: 29705512)
Cell. 1998 Sep 4;94(5):635-45. (PMID: 9741628)
Cell Rep. 2023 Jun 27;42(6):112535. (PMID: 37227821)
Development. 2015 May 15;142(10):1745-55. (PMID: 25968310)
J Cell Biol. 2011 Mar 21;192(6):939-48. (PMID: 21402789)
J Biochem Toxicol. 1991 Summer;6(2):83-92. (PMID: 1941903)
G3 (Bethesda). 2021 Feb 9;11(2):. (PMID: 33585875)
Chromosoma. 2011 Feb;120(1):1-21. (PMID: 21052706)
Cell. 2009 Oct 2;139(1):123-34. (PMID: 19804758)
Elife. 2023 Feb 15;12:. (PMID: 36790166)
Trends Cell Biol. 2021 May;31(5):387-401. (PMID: 33526340)
Dev Cell. 2018 Dec 17;47(6):785-800.e8. (PMID: 30416012)
Curr Biol. 2010 Dec 21;20(24):2159-68. (PMID: 21129974)
Nature. 2003 Sep 25;425(6956):411-4. (PMID: 14508492)
Chem Soc Rev. 2011 Jul;40(7):3496-508. (PMID: 21448484)
Int J Mol Sci. 2024 Jan 28;25(3):. (PMID: 38338890)
Curr Biol. 2012 Dec 4;22(23):2213-20. (PMID: 23141108)
Sci Adv. 2020 Oct 30;6(44):. (PMID: 33127680)
Nucleic Acids Res. 2025 Feb 08;53(4):. (PMID: 39964475)
Reprod Biomed Online. 2005 Feb;10(2):182-91. (PMID: 15823221)
Environ Health. 2017 Apr 7;16(1):37. (PMID: 28388912)
Genome Biol. 2014;15(12):550. (PMID: 25516281)
Cell Mol Life Sci. 2019 May;76(9):1729-1746. (PMID: 30810760)
Curr Protoc Toxicol. 2007 Feb;Chapter 1:Unit1.9. (PMID: 20922756)
G3 (Bethesda). 2023 Aug 9;13(8):. (PMID: 37284815)
Development. 2013 Apr;140(8):1645-54. (PMID: 23487310)
Cell Death Differ. 2019 Dec;26(12):2637-2651. (PMID: 30952991)
Chem Soc Rev. 2012 Mar 21;41(6):2135-71. (PMID: 22130572)
Environ Health Perspect. 2022 Jul;130(7):77005. (PMID: 35881550)
Cell Rep. 2018 May 22;23(8):2392-2404. (PMID: 29791850)
Nat Commun. 2021 Apr 13;12(1):2194. (PMID: 33850152)
Sci Total Environ. 2018 Mar;616-617:1089-1100. (PMID: 29100694)
J Mol Cell Biol. 2021 Dec 6;13(9):662-675. (PMID: 34081106)
Nucleic Acids Res. 2021 Sep 27;49(17):10082-10097. (PMID: 34478557)
Environ Toxicol Chem. 2021 Mar;40(3):606-630. (PMID: 33017053)
Ecotoxicol Environ Saf. 2021 Dec 1;225:112807. (PMID: 34562787)
Chem Biol Interact. 2018 Feb 1;281:1-10. (PMID: 29248446)
Nature. 2012 Sep 20;489(7416):447-51. (PMID: 22810588)
Toxicol Appl Pharmacol. 2022 Aug 15;449:116136. (PMID: 35752307)
Genetics. 2007 Aug;176(4):2015-25. (PMID: 17565948)
Science. 2006 Feb 10;311(5762):851-3. (PMID: 16469927)
Environ Int. 2022 Sep;167:107408. (PMID: 35908389)
Neuron. 2009 Jan 15;61(1):57-70. (PMID: 19146813)
Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10893-7. (PMID: 16037210)
Genome Biol. 2019 Mar 27;20(1):65. (PMID: 30917859)
Development. 1995 Aug;121(8):2525-35. (PMID: 7671816)
Nat Commun. 2018 Dec 14;9(1):5318. (PMID: 30552320)
Nat Commun. 2022 Sep 9;13(1):5306. (PMID: 36085149)
Adv Exp Med Biol. 2013;757:133-70. (PMID: 22872477)
iScience. 2020 Nov 19;23(12):101831. (PMID: 33305186)
Cell Death Differ. 2019 Oct;26(10):2157-2178. (PMID: 30728462)
WormBook. 2014 May 07;:1-49. (PMID: 24816713)
Nucleic Acids Res. 2023 Jul 5;51(W1):W419-W426. (PMID: 37125646)
Cell Prolif. 2023 Feb;56(2):e13353. (PMID: 36305033)
J Cell Biol. 2020 May 4;219(5):. (PMID: 32211900)
Environ Pollut. 2021 Sep 1;284:117508. (PMID: 34261219)
Environ Sci Pollut Res Int. 2021 Jan;28(2):1443-1453. (PMID: 32839910)
Genetics. 2017 May;206(1):163-178. (PMID: 28258184)
PLoS Genet. 2006 Nov 10;2(11):e174. (PMID: 17096596)
PLoS Genet. 2015 Mar 26;11(3):e1005078. (PMID: 25811365)
PLoS Genet. 2016 Jul 29;12(7):e1006223. (PMID: 27472198)
Environ Int. 2019 Oct;131:105048. (PMID: 31376596)
Elife. 2016 Feb 27;5:e12039. (PMID: 26920220)
Integr Environ Assess Manag. 2011 Oct;7(4):513-41. (PMID: 21793199)
Cell Discov. 2022 Apr 26;8(1):37. (PMID: 35473936)
EMBO J. 2023 Jun 1;42(11):e105002. (PMID: 37078421)
Genetics. 2007 Dec;177(4):2039-62. (PMID: 18073423)
Toxicol In Vitro. 2016 Sep;35:93-9. (PMID: 27233358)
Curr Biol. 2017 Jul 24;27(14):R720-R730. (PMID: 28743023)
Elife. 2020 Jul 31;9:. (PMID: 32735213)
Genetics. 2019 May;212(1):213-229. (PMID: 30867196)
Toxicol Res (Camb). 2015 May;4(3):645-654. (PMID: 25984295)
Dev Biol. 2011 Dec 1;360(1):195-207. (PMID: 21968099)
Methods Mol Biol. 2013;965:473-84. (PMID: 23296678)
Methods Mol Biol. 2022;2502:373-393. (PMID: 35412251)
PLoS Genet. 2007 Dec 28;3(12):e233. (PMID: 18166083)
Toxicol Sci. 2024 Nov 1;202(1):36-49. (PMID: 39141488)
Environ Health Perspect. 2013 Jun;121(6):717-24. (PMID: 23603051)
Hum Reprod Update. 2020 Sep 1;26(5):724-752. (PMID: 32476019)
Environ Int. 2022 Mar;161:107108. (PMID: 35121495)
Dev Biol. 2009 Feb 15;326(2):295-304. (PMID: 19100255)
Mol Reprod Dev. 2017 Jun;84(6):444-459. (PMID: 28379636)
Sci Rep. 2021 Jul 27;11(1):15241. (PMID: 34315935)
G3 (Bethesda). 2022 Aug 25;12(9):. (PMID: 35801939)
Environ Sci Technol. 2016 Mar 1;50(5):2396-404. (PMID: 26866980)
ACS Sustain Chem Eng. 2019 Mar 18;7(6):5808-5817. (PMID: 36419408)
Dev Cell. 2013 Oct 28;27(2):227-240. (PMID: 24120884)
J Vis Exp. 2016 Nov 29;(117):. (PMID: 27929466)
Environ Res. 2019 Jan;168:406-413. (PMID: 30388497)
J Phys Chem B. 2007 Jul 19;111(28):8045-52. (PMID: 17585796)
Genetics. 2020 Jul;215(3):531-568. (PMID: 32632025)
Chemosphere. 2016 Feb;144:2384-91. (PMID: 26610298)
Environ Sci Technol. 2018 Jul 17;52(14):7621-7629. (PMID: 29749740)
J Photochem Photobiol B. 2016 Jun;159:66-73. (PMID: 27031195)
Bioinformatics. 2016 Mar 15;32(6):943-5. (PMID: 26559506)
Nat Methods. 2017 Apr;14(4):417-419. (PMID: 28263959)
Dev Biol. 2005 Mar 15;279(2):322-35. (PMID: 15733661)
Sci Total Environ. 2023 May 15;873:162439. (PMID: 36848992)
Dev Biol. 2016 Oct 15;418(2):248-257. (PMID: 27521456)
Curr Biol. 2010 Jul 27;20(14):1321-5. (PMID: 20579881)
Elife. 2020 Apr 27;9:. (PMID: 32338603)
PLoS Genet. 2012 May;8(5):e1002742. (PMID: 22693456)
Nucleic Acids Res. 2022 Jul 5;50(W1):W710-W717. (PMID: 35556129)
Environ Sci Technol. 2019 Jan 15;53(2):760-770. (PMID: 30572703)
Reprod Toxicol. 2024 Jun;126:108602. (PMID: 38723698)
Reprod Toxicol. 2019 Dec;90:24-32. (PMID: 31445225)
Elife. 2017 Jan 03;6:. (PMID: 28045371)
Sci Rep. 2017 Aug 29;7(1):9839. (PMID: 28852193)
Science. 2001 Mar 16;291(5511):2144-7. (PMID: 11251118)
Environ Sci Technol. 2017 Aug 1;51(15):8782-8794. (PMID: 28654245)
Cell. 2017 Apr 20;169(3):457-469.e13. (PMID: 28431246)
Cell. 1998 Sep 4;94(5):635-45. (PMID: 9741628)
Cell Rep. 2023 Jun 27;42(6):112535. (PMID: 37227821)
Development. 2015 May 15;142(10):1745-55. (PMID: 25968310)
J Cell Biol. 2011 Mar 21;192(6):939-48. (PMID: 21402789)
J Biochem Toxicol. 1991 Summer;6(2):83-92. (PMID: 1941903)
G3 (Bethesda). 2021 Feb 9;11(2):. (PMID: 33585875)
Chromosoma. 2011 Feb;120(1):1-21. (PMID: 21052706)
Cell. 2009 Oct 2;139(1):123-34. (PMID: 19804758)
Elife. 2023 Feb 15;12:. (PMID: 36790166)
Trends Cell Biol. 2021 May;31(5):387-401. (PMID: 33526340)
Dev Cell. 2018 Dec 17;47(6):785-800.e8. (PMID: 30416012)
Curr Biol. 2010 Dec 21;20(24):2159-68. (PMID: 21129974)
Nature. 2003 Sep 25;425(6956):411-4. (PMID: 14508492)
Chem Soc Rev. 2011 Jul;40(7):3496-508. (PMID: 21448484)
Int J Mol Sci. 2024 Jan 28;25(3):. (PMID: 38338890)
Curr Biol. 2012 Dec 4;22(23):2213-20. (PMID: 23141108)
Sci Adv. 2020 Oct 30;6(44):. (PMID: 33127680)
Nucleic Acids Res. 2025 Feb 08;53(4):. (PMID: 39964475)
Reprod Biomed Online. 2005 Feb;10(2):182-91. (PMID: 15823221)
Environ Health. 2017 Apr 7;16(1):37. (PMID: 28388912)
Genome Biol. 2014;15(12):550. (PMID: 25516281)
Cell Mol Life Sci. 2019 May;76(9):1729-1746. (PMID: 30810760)
Curr Protoc Toxicol. 2007 Feb;Chapter 1:Unit1.9. (PMID: 20922756)
G3 (Bethesda). 2023 Aug 9;13(8):. (PMID: 37284815)
Development. 2013 Apr;140(8):1645-54. (PMID: 23487310)
Cell Death Differ. 2019 Dec;26(12):2637-2651. (PMID: 30952991)
Chem Soc Rev. 2012 Mar 21;41(6):2135-71. (PMID: 22130572)
Environ Health Perspect. 2022 Jul;130(7):77005. (PMID: 35881550)
Cell Rep. 2018 May 22;23(8):2392-2404. (PMID: 29791850)
Nat Commun. 2021 Apr 13;12(1):2194. (PMID: 33850152)
Sci Total Environ. 2018 Mar;616-617:1089-1100. (PMID: 29100694)
J Mol Cell Biol. 2021 Dec 6;13(9):662-675. (PMID: 34081106)
Nucleic Acids Res. 2021 Sep 27;49(17):10082-10097. (PMID: 34478557)
Environ Toxicol Chem. 2021 Mar;40(3):606-630. (PMID: 33017053)
Ecotoxicol Environ Saf. 2021 Dec 1;225:112807. (PMID: 34562787)
Chem Biol Interact. 2018 Feb 1;281:1-10. (PMID: 29248446)
Nature. 2012 Sep 20;489(7416):447-51. (PMID: 22810588)
Toxicol Appl Pharmacol. 2022 Aug 15;449:116136. (PMID: 35752307)
Genetics. 2007 Aug;176(4):2015-25. (PMID: 17565948)
Science. 2006 Feb 10;311(5762):851-3. (PMID: 16469927)
Environ Int. 2022 Sep;167:107408. (PMID: 35908389)
Neuron. 2009 Jan 15;61(1):57-70. (PMID: 19146813)
Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10893-7. (PMID: 16037210)
Genome Biol. 2019 Mar 27;20(1):65. (PMID: 30917859)
Development. 1995 Aug;121(8):2525-35. (PMID: 7671816)
Nat Commun. 2018 Dec 14;9(1):5318. (PMID: 30552320)
Nat Commun. 2022 Sep 9;13(1):5306. (PMID: 36085149)
Adv Exp Med Biol. 2013;757:133-70. (PMID: 22872477)
iScience. 2020 Nov 19;23(12):101831. (PMID: 33305186)
Cell Death Differ. 2019 Oct;26(10):2157-2178. (PMID: 30728462)
WormBook. 2014 May 07;:1-49. (PMID: 24816713)
Nucleic Acids Res. 2023 Jul 5;51(W1):W419-W426. (PMID: 37125646)
Cell Prolif. 2023 Feb;56(2):e13353. (PMID: 36305033)
J Cell Biol. 2020 May 4;219(5):. (PMID: 32211900)
Environ Pollut. 2021 Sep 1;284:117508. (PMID: 34261219)
Environ Sci Pollut Res Int. 2021 Jan;28(2):1443-1453. (PMID: 32839910)
Genetics. 2017 May;206(1):163-178. (PMID: 28258184)
PLoS Genet. 2006 Nov 10;2(11):e174. (PMID: 17096596)
PLoS Genet. 2015 Mar 26;11(3):e1005078. (PMID: 25811365)
PLoS Genet. 2016 Jul 29;12(7):e1006223. (PMID: 27472198)
Environ Int. 2019 Oct;131:105048. (PMID: 31376596)
Elife. 2016 Feb 27;5:e12039. (PMID: 26920220)
Integr Environ Assess Manag. 2011 Oct;7(4):513-41. (PMID: 21793199)
Cell Discov. 2022 Apr 26;8(1):37. (PMID: 35473936)
EMBO J. 2023 Jun 1;42(11):e105002. (PMID: 37078421)
Genetics. 2007 Dec;177(4):2039-62. (PMID: 18073423)
Toxicol In Vitro. 2016 Sep;35:93-9. (PMID: 27233358)
Curr Biol. 2017 Jul 24;27(14):R720-R730. (PMID: 28743023)
Elife. 2020 Jul 31;9:. (PMID: 32735213)
Genetics. 2019 May;212(1):213-229. (PMID: 30867196)
Toxicol Res (Camb). 2015 May;4(3):645-654. (PMID: 25984295)
Dev Biol. 2011 Dec 1;360(1):195-207. (PMID: 21968099)
Methods Mol Biol. 2013;965:473-84. (PMID: 23296678)
Methods Mol Biol. 2022;2502:373-393. (PMID: 35412251)
PLoS Genet. 2007 Dec 28;3(12):e233. (PMID: 18166083)
Toxicol Sci. 2024 Nov 1;202(1):36-49. (PMID: 39141488)
Environ Health Perspect. 2013 Jun;121(6):717-24. (PMID: 23603051)
Hum Reprod Update. 2020 Sep 1;26(5):724-752. (PMID: 32476019)
Environ Int. 2022 Mar;161:107108. (PMID: 35121495)
Dev Biol. 2009 Feb 15;326(2):295-304. (PMID: 19100255)
Mol Reprod Dev. 2017 Jun;84(6):444-459. (PMID: 28379636)
Sci Rep. 2021 Jul 27;11(1):15241. (PMID: 34315935)
G3 (Bethesda). 2022 Aug 25;12(9):. (PMID: 35801939)
Environ Sci Technol. 2016 Mar 1;50(5):2396-404. (PMID: 26866980)
ACS Sustain Chem Eng. 2019 Mar 18;7(6):5808-5817. (PMID: 36419408)
Dev Cell. 2013 Oct 28;27(2):227-240. (PMID: 24120884)
J Vis Exp. 2016 Nov 29;(117):. (PMID: 27929466)
Environ Res. 2019 Jan;168:406-413. (PMID: 30388497)
J Phys Chem B. 2007 Jul 19;111(28):8045-52. (PMID: 17585796)
Genetics. 2020 Jul;215(3):531-568. (PMID: 32632025)
Chemosphere. 2016 Feb;144:2384-91. (PMID: 26610298)
Environ Sci Technol. 2018 Jul 17;52(14):7621-7629. (PMID: 29749740)
J Photochem Photobiol B. 2016 Jun;159:66-73. (PMID: 27031195)
Bioinformatics. 2016 Mar 15;32(6):943-5. (PMID: 26559506)
Nat Methods. 2017 Apr;14(4):417-419. (PMID: 28263959)
Dev Biol. 2005 Mar 15;279(2):322-35. (PMID: 15733661)
Sci Total Environ. 2023 May 15;873:162439. (PMID: 36848992)
Dev Biol. 2016 Oct 15;418(2):248-257. (PMID: 27521456)
Curr Biol. 2010 Jul 27;20(14):1321-5. (PMID: 20579881)
Elife. 2020 Apr 27;9:. (PMID: 32338603)
PLoS Genet. 2012 May;8(5):e1002742. (PMID: 22693456)
Nucleic Acids Res. 2022 Jul 5;50(W1):W710-W717. (PMID: 35556129)
Environ Sci Technol. 2019 Jan 15;53(2):760-770. (PMID: 30572703)
Reprod Toxicol. 2024 Jun;126:108602. (PMID: 38723698)
Reprod Toxicol. 2019 Dec;90:24-32. (PMID: 31445225)
Elife. 2017 Jan 03;6:. (PMID: 28045371)
Sci Rep. 2017 Aug 29;7(1):9839. (PMID: 28852193)
Science. 2001 Mar 16;291(5511):2144-7. (PMID: 11251118)
Environ Sci Technol. 2017 Aug 1;51(15):8782-8794. (PMID: 28654245)
Cell. 2017 Apr 20;169(3):457-469.e13. (PMID: 28431246)
Grant Information:
P40 OD010440 United States RI ORIP NIH HHS; John Templeton Foundation; R01 ES027487 United States ES NIEHS NIH HHS; P40 OD010440 United States OD NIH HHS; T32 ES015457 United States ES NIEHS NIH HHS; R01 ES034251 United States ES NIEHS NIH HHS; National Institute of Health; R01ES034251 United States ES NIEHS NIH HHS; R01ES027487 United States ES NIEHS NIH HHS; Burroughs Wellcome Innovation in Regulatory Science; NIH; T32ES015457 National Institute of Environmental Health Sciences Molecular Toxicology Training Program
Contributed Indexing:
Keywords: PFAS; biological condensates; germ cells; reproduction; toxicogenomics
Substance Nomenclature:
0 (Fluorocarbons)
0 (Alkanesulfonic Acids)
9H2MAI21CL (perfluorooctane sulfonic acid)
0 (Environmental Pollutants)
0 (Alkanesulfonic Acids)
9H2MAI21CL (perfluorooctane sulfonic acid)
0 (Environmental Pollutants)
Entry Date(s):
Date Created: 20250730 Date Completed: 20251113 Latest Revision: 20251114
Update Code:
20251114
PubMed Central ID:
PMC12599869
DOI:
10.1093/toxsci/kfaf111
PMID:
40737503
Database:
MEDLINE
Weitere Informationen
Per- and polyfluoroalkyl substances (PFAS) are highly persistent in the environment and widespread in consumer products, environmental media, and biological samples. However, limited toxicology data exist for many of the over 15,000 chemicals belonging to the PFAS family. Data are particularly lacking for exposures during germ cell development, which can have consequences for later-life fecundity. Here, we leverage the tractability of the model organism Caenorhabditis elegans to compare a "legacy" PFAS, i.e. perfluorooctane sulfonic acid (PFOS), with a chlorinated ether analog, 6:2 chlorinated polyfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA). We consistently observed negative effects of both PFOS and 6:2 Cl-PFESA on germ cell numbers along with increases in germline apoptosis and defective meiotic progression. These cellular observations corresponded with increases in embryonic lethality in offspring from developmentally exposed adults. Messenger RNA and small RNA sequencing revealed a clear signature of perturbation of the non-coding RNA-mediated germline regulatory network consistent with observed ex vivo disruption of P granules, liquid-like assemblages of RNA, and protein. Remarkably, we identified a strong gene-environment interaction between PFOS and 6:2 Cl-PFESA with another liquid-like structure, the synaptonemal complex (SC); syp3(OK758) hypomorphic mutants exhibited near-complete embryonic lethality with PFAS exposure. Thus, while performed at relatively high concentrations to ensure robust effect detection, our mechanistic findings provide a foundation for understanding the reproductive toxicity of PFAS across exposure scenarios. Altogether, our data show that the impacts of PFAS on germ cell development and function are associated with perturbation of liquid-like condensates, suggesting that PFAS physicochemical properties may contribute to their pleiotropic effects on biological systems.
(© The Author(s) 2025. Published by Oxford University Press on behalf of the Society of Toxicology.)