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Sperm production is comprised in mice exposed to environmentally relevant per- and polyfluoroalkyl substances (PFAS)

ABSTRACT: Per- and polyfluoroalkyl substances (PFAS) are a large group of persistent synthetic chemicals that are ubiquitous environmental contaminants. Mounting evidence demonstrates that PFAS can bioaccumulate and induce a suite of adverse health outcomes, including compromise of male reproduction. Despite this knowledge, there remains no clear consensus as to how PFAS elicit these responses. Accordingly, here we aimed to determine how an environmentally relevant cocktail of PFAS impact the fertility of male mice. After twelve weeks of continuous PFAS exposure, blood plasma was isolated for hormone and PFAS profiling and reproductive tissues and spermatozoa were subjected to a comprehensive battery of histological and functional analyses. These analyses revealed that PFAS exposure significantly reduced the rate of daily sperm production linked with reduced levels of circulating testosterone and dihydrotestosterone. Functional profiling of mature spermatozoa from PFAS exposed males failed to identify any overt changes in sperm viability, motility, DNA integrity, or ability to undergo capacitation and support in vitro fertilization and early embryonic development. PFAS exposed spermatozoa did, however, present with pronounced changes in their small non-coding RNA profile and were linked with significant dysregulation of early embryonic gene expression. These observations afford new mechanistic insight into how PFAS exposure impacts male reproductive health.

ORGANISM(S): Mus musculus

PROVIDER: GSE271479 | GEO | 2025/08/31

REPOSITORIES: GEO

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Project description:Per- and polyfluoroalkyl substances (PFAS) are some of the most prominent organic contaminants in human blood that have the potential to disrupt biological processes and pathways in the liver. Although the toxicological implications from human exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are well established, data on other, lesser-understood PFAS are limited. A challenge for regulatory authorities is to determine acceptable levels of human exposure to large, diverse classes of environmental contaminants. New approach methodologies (NAMs) that apply bioinformatics tools to interpret biological data are being increasingly considered to inform risk assessment when traditional toxicology methodologies are not amenable. The aim of the current investigation was to identify the biological responses relevant to PFAS mode of action as the concentration (benchmark dose) that these effects take place in order to utililze this information to inform/facilitate read-across for risk assessment of data-poor PFAS. A TempO-Seq platform (BioSpyder) measured gene expression changes in human liver microtissues (i.e., spheroids) after 1-day and 10-day exposures to increasing concentrations of PFAS. A bioinformatics framework was applied to 23 PFAS sub-classed into carboxylates (PFCAs), sulfonates (PFSAs), or PFAS precursors that were analyzed for the total altered transcripts, the concentration where effects take place, and identifying target genes of interest. Both PFCAs and PFSAs exhibited a trend toward increased transcriptional changes with carbon chain-length. Specifically, longer-chain compounds (7 to 10 carbons) were more likely to surpass liver-toxic transcriptomic thresholds established from previous studies than shorter chain PFAS. Longer-chain PFAS were also more potent, inducing transcriptional effects at lower concentrations. However, PFOS was the most potent PFAS and of all precursors, only PFOSA (a PFOS precursor) induced a response. The combined high-throughput transcriptomic and bioinformatics analyses revealed the capability of NAMs to assess the effects of PFAS in liver microtissues; such data improves our understanding of PFAS-related effects in humans and facilitates the use of read-across in human health risk assessment for other data-poor chemicals.

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Sperm production is comprised in mice exposed to environmentally relevant per- and polyfluoroalkyl substances (PFAS)

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