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

Steves, Alyse N.; Turry, Adam; Gill, Brittany; Clarkson-Townsend, Danielle; Bradner, Joshua M.; Bachli, Ian; Caudle, W. Michael; Miller, Gary W.; Chan, Anthony W.S.; Easley, Charles A.

doi:10.1080/19396368.2018.1481465

Cited by 40 publications

(22 citation statements)

References 63 publications

(119 reference statements)

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“…hESCs were pasaged using ReLeSR (STEMCELL Technologies) and plated onto Matrigel (Corning Life Sciences) coated plates as described 32,34 . Differentiation into spermatogenic lineages were conducted as previously described [32][33][34][35] with mouse STO cells for feeder cells or directly onto Matrigel. Medium was gassed every other day with a blood gas mixture (5% carbon dioxide, 5% oxygen, and 90% nitrogen).…”

Section: Methodsmentioning

confidence: 99%

“…We were then able to simulate male exposure by differentiating WA01 human embryonic stem cells in the presence of 2,2′,4,4′,5,5′-hexabromobiphenyl (PBB153), into spermatogonial stem cells, primary and secondary spermatocytes and, finally, into spermatids. We previously demonstrated that this model mimics major components of human spermatogenesis 32 and have utilized this model to examine impacts of other environmental exposures [33][34][35] . Additionally, our in vitro spermatogenesis model has been independently replicated, highlighting its reproducibility 36 .…”

Section: Pbb153 Decreases Methylation At Icrs Of Imprinting Genes In mentioning

confidence: 99%

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Detrimental effects of flame retardant, PBB153, exposure on sperm and future generations

Greeson

Fowler

Estave

et al. 2020

Sci Rep

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In 1973, the Velsicol Chemical Company, which manufactured FireMaster, a brominated flame retardant, and NutriMaster, a nutritional supplement, mistakenly shipped hundreds of pounds of FireMaster to grain mills around Michigan where it was incorporated into animal feed and then into the food chain across the state. An estimated 6.5 million Michigan residents consumed polybrominated biphenyl (PBB)-laced animal products leading to one of the largest agricultural accidents in U.S. history. To date, there have been no studies investigating the effects of PBB on epigenetic regulation in sperm, which could explain some of the endocrine-related health effects observed among children of PBB-exposed parents. Fusing epidemiological approaches with a novel in vitro model of human spermatogenesis, we demonstrate that exposure to PBB153, the primary component of FireMaster, alters the epigenome in human spermatogenic cells. Using our novel stem cell-based spermatogenesis model, we show that PBB153 exposure decreases DNA methylation at regulatory elements controlling imprinted genes. Furthermore, PBB153 affects DNA methylation by reducing de novo DNA methyltransferase activity at increasing PBB153 concentrations as well as reducing maintenance DNA methyltransferase activity at the lowest tested PBB153 concentration. Additionally, PBB153 exposure alters the expression of genes critical to proper human development. Taken together, these results suggest that PBB153 exposure alters the epigenome by disrupting methyltransferase activity leading to defects in imprint establishment causing altered gene expression, which could contribute to health concerns in the children of men exposed to PBB153. While this chemical is toxic to those directly exposed, the results from this study indicate that the epigenetic repercussions may be detrimental to future generations. Above all, this model may be expanded to model a multitude of environmental exposures to elucidate the effect of various chemicals on germline epigenetics and how paternal exposure may impact the health of future generations. In recent years, a major focus of research has been the Developmental Origins of Health and Disease (DOHaD) 1. A component of DOHaD research examines the impact of pre-and post-conception risk factors on long-term health and disease progression in adulthood. In terms of pre-conception risk factors, many researchers report that toxicants and environmental exposures can potentially alter the epigenome in gametes, giving these exposures the potential to ultimately impact the health of the next generation 2-5. In 1973, farms across Michigan mistakenly received cattle feed mixed with FireMaster BP-6, a chemical flame retardant composed of a mixture of polybrominated biphenyl compounds (PBBs), rather than NutriMaster, a food additive that increased milk production in farm animals 6-9. PBB-laced animal products were consumed by millions of residents, and the decline in animal

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Section: Methodsmentioning

confidence: 99%

Section: Pbb153 Decreases Methylation At Icrs Of Imprinting Genes In mentioning

confidence: 99%

Detrimental effects of flame retardant, PBB153, exposure on sperm and future generations

Greeson

Fowler

Estave

et al. 2020

Sci Rep

Self Cite

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“…Molecular mechanisms of PFASs reproductivity are poorly known, and the number of publications reporting their effect on the human reproductive system is limited. Analyses with the use of the innovative in vitro model of spermatogenesis carried out on stem cells indicated that PFASs (PFOS, PFOA and PFNA), independently and as a mixture, caused no changes of transmembrane mitochondrial potential, did not intensify reactive oxygen species (ROS) generation and did not decrease viability of spermatogonia, spermatocytes (primary and secondary) or spermatidia [ 209 ]. However, this study demonstrated that selected PFASs could have a long-term effect on fertility by exhaustion of spermatogonia pool and by disturbance of function of primary spermatocytes caused by reduction of expression of markers specific for these cells.…”

Section: Endocrine Disruption Caused By Pfassmentioning

confidence: 99%

Endocrine Disruptor Potential of Short- and Long-Chain Perfluoroalkyl Substances (PFASs)—A Synthesis of Current Knowledge with Proposal of Molecular Mechanism

Mokra

2021

IJMS

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Endocrine disruptors are a group of chemical compounds that, even in low concentrations, cause a hormonal imbalance in the body, contributing to the development of various harmful health disorders. Many industry compounds, due to their important commercial value and numerous applications, are produced on a global scale, while the mechanism of their endocrine action has not been fully understood. In recent years, per- and polyfluoroalkyl substances (PFASs) have gained the interest of major international health organizations, and thus more and more studies have been aimed to explain the toxicity of these compounds. PFASs were firstly synthesized in the 1950s and broadly used in the industry in the production of firefighting agents, cosmetics and herbicides. The numerous industrial applications of PFASs, combined with the exceptionally long half-life of these substances in the human body and extreme environmental persistence, result in a common and chronic exposure of the general population to their action. Available data have suggested that human exposure to PFASs can occur during different stages of development and may cause short- or/and long-term health effects. This paper synthetizes the current literature reports on the presence, bioaccumulation and, particularly, endocrine toxicity of selected long- and short-chain PFASs, with a special emphasis on the mechanisms underlying their endocrine actions.

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“…Epidemiological studies have linked PFAS exposure to increased cholesterol levels[47]. SSCs exposed to PFAS did not experience a decrease in germ cell viability, an increase in reactive oxygen species (ROS), or reduced cell viability[48].…”

Section: Heavy Metalsmentioning

confidence: 99%

Effects of environmental stressors on stem cells

Worley

Parker

2019

WJSC

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Environmental toxicants are ubiquitous, and many are known to cause harmful health effects. However, much of what we know or think we know concerning the targets and long-term effects of exposure to environmental stressors is sadly lacking. Toxicant exposure may have health effects that are currently mischaracterized or at least mechanistically incompletely understood. While much of the recent excitement about stem cells (SCs) focuses on their potential as therapeutic agents, they also offer a valuable resource to give us insight into the mechanisms and risks of toxicant effects. Not only as a response to the increasing ethical pressure to reduce animal testing, SC studies allow us valuable insight into the true effects of human exposure to environmental stressors under controlled conditions. We present a review of the history of publications on the effects of environmental stressors on SCs, followed by a consolidation of the literature over the past five years on a subset of key environmental stressors of importance to human health and their effects on both embryonic and tissue SCs. The review will make constructive suggestions as to areas of toxicant research where further studies are needed, as well as making indications of the potential utility for advancing knowledge and directing research on environmental toxicology.

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

Cited by 40 publications

References 63 publications

Detrimental effects of flame retardant, PBB153, exposure on sperm and future generations

Detrimental effects of flame retardant, PBB153, exposure on sperm and future generations

Endocrine Disruptor Potential of Short- and Long-Chain Perfluoroalkyl Substances (PFASs)—A Synthesis of Current Knowledge with Proposal of Molecular Mechanism

Effects of environmental stressors on stem cells

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