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Author Notes:

Charles A. Easley IV, University of Georgia, Edgar L. Rhodes Center for Animal and Dairy Science, 425 River Road, Room 450, Athens, GA 30602, Telephone: (706) 542-2725, Fax: (706) 542-6730, cae25@uga.edu.

Designed and conducted experiments and wrote the paper: AS; Conducted experiments and wrote the paper: AT, BG; Designed and conducted experiments: DC; Conducted experiments: JB, IB; Designed experiments: GM, WMC; Designed experiments and served as the primary mentors to AS:AC, CE.

The authors report no conflict of interest.

Subjects:

Research Funding:

This work was supported by the National Science Foundation under Grant DGE-1444932; the National Institutes of Health under Grant 1K22 ES025418-01; Emory University’s Atlanta Clinical & Translational Science Institute and University Research Committee (ACTSI/URC) award; and the National Institutes of Health under Grant P30 ES019776-01-A1.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Andrology
  • Reproductive Biology
  • Endocrinology & Metabolism
  • Perfluorooctanesulfonic acid (PFOS)
  • perfluorooctanoic acid (PFOA)
  • perfluorononanoic acid (PFNA)
  • in vitro spermatogenesis
  • male reproductive toxicity
  • HUMAN SEMEN QUALITY
  • PERFLUORINATED CARBOXYLIC-ACIDS
  • PERFLUOROOCTANE SULFONATE PFOS
  • WASTE-WATER TREATMENT
  • BLOOD-TESTIS BARRIER
  • OXIDATIVE STRESS
  • IN-VITRO
  • PERFLUOROALKYL SUBSTANCES
  • PERFLUORONONANOIC ACID
  • EUROPEAN POPULATIONS

Per- and polyfluoroalkyl substances impact human spermatogenesis in a stem-cell-derived mode

Journal Title:

Systems Biology in Reproductive Medicine

Volume:

Volume 64, Number 4

Publisher:

, Pages 225-239

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Per- and polyfluoroalkyl substances (PFASs) represent a highly ubiquitous group of synthetic chemicals used in products ranging from water and oil repellents and lubricants to firefighting foam. These substances can enter and accumulate in multiple tissue matrices in up to 100% of people assessed. Though animal models strongly identify these compounds as male reproductive toxicants, with exposed rodents experiencing declines in sperm count, alterations in hormones, and DNA damage in spermatids, among other adverse outcomes, human studies report conflicting conclusions as to the reproductive toxicity of these chemicals. Using an innovative, human stem-cell-based model of spermatogenesis, we assessed the effects of the PFASs perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and a mixture of PFOS, PFOA, and PFNA for their impacts on human spermatogenesis in vitro under conditions relevant to the general and occupationally exposed populations. Here, we show that PFOS, PFOA, PFNA, and a mixture of PFOS, PFOA, and PFNA do not decrease in vitro germ cell viability, consistent with reports from human studies. These compounds do not affect mitochondrial membrane potential or increase reactive oxygen species generation, and they do not decrease cell viability of spermatogonia, primary spermatocytes, secondary spermatocytes, or spermatids in vitro under the conditions examined. However, exposure to PFOS, PFOA, and PFNA reduces expression of markers for spermatogonia and primary spermatocytes. While not having direct effects on germ cell viability, these effects suggest the potential for long-term impacts on male fertility through the exhaustion of the spermatogonial stem cell pool and abnormalities in primary spermatocytes. Abbreviations: CDC: Centers for Disease Control; DMSO: dimethyl sulfoxide; GHR: growth hormone receptor; hESCs: human embryonic stem cells; PFASs: per- and polyfluoroalkyl substances; PFCs: perfluorinated compounds; PFNA: perfluorononanoic acid; PFOS: perfluorooctanesulfonic acid; PFOA: perfluorooctanoic acid; PLZF: promyelocytic leukemia zinc finger; ROS: reactive oxygen species; HILI: RNA-mediated gene silencing 2; SSC: spermatogonial stem cell.

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