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BRB-seq analysis of PFOS disruption of key developmental pathways during hiPSC-derived cardiomyocyte differentiation

ABSTRACT: Exposure to per- and polyfluoroalkyl substances (PFASs) such as perfluorooctanesulfonic acid (PFOS) has been associated with congenital heart disease (CHD) and decreased birth weight. PFAS exposure can disrupt signaling pathways relevant for cardiac development in stem cell derived cardiomyocyte assays, including PFOS-induced disruption to in vitro cardiac differentiation into contracting spheroids of cardiomyocytes; the PluriBeat assay. Notably, cell line origin can affect how the assay respond to PFAS exposure. Herein, we examine the effect of PFOS on cardiomyocyte differentiation by transcriptomics profiling of two different human induced pluripotent stem cell (hiPSC) lines, to see if they exhibit a common pattern of disruption. Two stages of differentiation, the cardiac progenitor stage (early) and the cardiomyocyte stage (late), were investigated.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202077 | GEO | 2022/05/03

REPOSITORIES: GEO

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Project description:The potential effects of poly- and perfluoroalkyl substances (PFAS) are a recent human and environmental health concern. There is a persistent link between PFAS exposure and cancer, but the mechanisms are poorly understood. Although epidemiological evidence supporting PFAS exposure and cancer in general is conflicting, there is a relatively strong evidence linking PFAS and testicular germ cell tumors (TGCTs). However, there have been no mechanistic studies to date cancerning PFAS and TGCTs. In this report, the effects of the legacy PFAS, perfluorooctanesulfonic acid (PFOS) and the newer "clean energy" PFAS, lithium bis(trifluoromethylsulfonyl)imide (LiTFSi and called HQ-115) on TGCT tumorigenicity, survival, metabolism, and gene regulation were investigated. In vitro, proliferation and survival of both chemo-sensitive and -resistant TGCT cells were minimally affected by a wide concentration range of PFOS and HQ-115. However, both chemicals promoted the growth of TGCT cells in mouse xenografts at doses consistenet with human exposure but had minimal acute toxicity, as assessed by total body, kidney, and testis weight. PFOS, but not HQ-115, increased liver weight. Transcriptiomic alterations of PFOS-exposed normal mouse testes were dominated by cancer-related pathways and gene expression altersations associated with the H3K27me3 polycomb pathway and DNA methylation, epigenetic pathways were previously shown to be critical for the survival of TGCT cells after cisplatin-based chemotherapy. Similar pattersn of PFOS-mediated gene expression occured in PFOS-exposed cells in vitro. Metabolomic studies revealed that PFOS also altered metabolites associiated with steroid biosynthesis and fatty acid metabolism in TGCT cells, consistent with the proposed ability of PFAS to mimic fatty acied based ligands controlling lipid metabolism and the proposed role of PFAS as endocrine disrupters. Our data, this first cell and animal based study on PFAS in TGCTs, support a pro-tumorigenic effect of PFAS on TGCT biology and suggests epigenetic, metabolic, and endocrine disruption as potential mechanisms of action that are consistent with the non-mutagenic nature of the PFAS class.

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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BRB-seq analysis of PFOS disruption of key developmental pathways during hiPSC-derived cardiomyocyte differentiation

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