Vascular endothelium as a target for perfluroalkyl substances (PFAs)

Wittkopp, Sharine; Wu, Fen; Windheim, Joseph; Robinson, Morgan; Kannan, Kurunthachalam; Katz, Stuart D.; Chen, Yu; Newman, Jonathan

doi:10.1016/j.envres.2022.113339

Cited by 6 publications

(5 citation statements)

References 17 publications

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“…Several studies have investigated PFAS associations with cardiovascular intermediates or risk factors rather than CVD hard endpoints (Table 3). These studies have indicated associations between PFAS and platelet dysfunction, 21 endothelial damage, 22,23 carotid artery thickness and artery calcification (a measure of atherosclerosis) 24 . These findings again point towards more of a positive association between PFAS and CVD, in line with most of the cross‐sectional studies, and give insight into potential mechanistic pathways (discussed further in Section 3: molecular mechanisms).…”

Section: Epidemiological Evidence and Considerationssupporting

confidence: 54%

“…De Toni (2020) 21 ; Lin (2016) 22 ; Wittkopp (2022) 23 Toxicokinetics not taken into account Abbreviations: CVD, cardiovascular disease; PFAS, per-and polyfluoroalkyl substances.…”

Section: Reference Study Set-up Main Results Notementioning

confidence: 99%

“…Several studies have investigated PFAS associations with cardiovascular intermediates or risk factors rather than CVD hard endpoints (Table 3). These studies have indicated associations between PFAS and platelet dysfunction, 21 endothelial damage, 22,23 carotid artery thickness and artery calcification (a measure of atherosclerosis). 24 These findings again point towards more of a F I G U R E 1 Forest plot showing results of a random effects meta-analysis of published prospective studies on associations of PFOA with CVD outcomes.…”

Section: Cvdmentioning

confidence: 99%

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Per‐ and polyfluoroalkyl substances and cardiometabolic diseases: A review

Schillemans,

Donat‐Vargas,

Åkesson

2023

Basic Clin Pharma Tox

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Per‐ and polyfluoroalkyl substances (PFAS) are a group of persistent and widespread environmental pollutants that represent a high concern for human health. They have been shown to be associated with several important physiological processes such as lipid metabolism and the immune system. Consequently, PFAS are suspected to play a role in cardiometabolic disease development. However, the evidence regarding associations between PFAS and overt cardiovascular disease and type 2 diabetes remains limited and inconsistent. To address this, we conducted a review of the epidemiological evidence. A deeper understanding of potential underlying molecular mechanisms may help to explain inconsistencies in epidemiological findings. Thus, to gain more mechanistic insight, we also summarized evidence from omics and laboratory studies into an adverse outcome pathway framework. Our observations indicate the potential for associations of PFAS with multiple molecular pathways that could have opposite associations with disease risk, which could be further modified by mixture composition, lifestyle factors or genetic polymorphisms. This identifies the need for exposome studies considering mixture effects, the use of multi‐omics data to gain insight in relevant pathways and the integration of epidemiological and laboratory studies to enhance mechanistic understanding and causal inference. Improved comprehension is essential for environmental health risk assessments.

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Section: Epidemiological Evidence and Considerationssupporting

confidence: 54%

“…De Toni (2020) 21 ; Lin (2016) 22 ; Wittkopp (2022) 23 Toxicokinetics not taken into account Abbreviations: CVD, cardiovascular disease; PFAS, per-and polyfluoroalkyl substances.…”

Section: Reference Study Set-up Main Results Notementioning

confidence: 99%

“…Several studies have investigated PFAS associations with cardiovascular intermediates or risk factors rather than CVD hard endpoints (Table 3). These studies have indicated associations between PFAS and platelet dysfunction, 21 endothelial damage, 22,23 carotid artery thickness and artery calcification (a measure of atherosclerosis). 24 These findings again point towards more of a F I G U R E 1 Forest plot showing results of a random effects meta-analysis of published prospective studies on associations of PFOA with CVD outcomes.…”

Section: Cvdmentioning

confidence: 99%

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Per‐ and polyfluoroalkyl substances and cardiometabolic diseases: A review

Schillemans,

Donat‐Vargas,

Åkesson

2023

Basic Clin Pharma Tox

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“…Association between low oxygen and low birth weight has also been reported . However, the understanding of PFAS-induced vascular toxicity and blood oxygen alteration is currently insufficient, with only a few in vitro studies on vascular toxicity and none on blood oxygen alteration conducted thus far. ,,, Suggestive pieces of evidence have been reported that PFOS exposure can decrease gene expression of the potent angiogenic factor in placental multinucleated syncytial BeWo cells, hinting the potential vascular disrupting effects . Similarly, PFOA can induce morphological changes and stalk sprouting in the vascular three-dimensional-network structure established using the HTR-8/SVneo cell line (human chorionic villous trophoblasts) via activation of the NOTCH-signaling pathway .…”

Section: Discussionmentioning

confidence: 99%

Unveiling Distribution of Per- and Polyfluoroalkyl Substances in Matched Placenta-Serum Tetrads: Novel Implications for Birth Outcome Mediated by Placental Vascular Disruption

Pan

Qiu

et al. 2023

Environ. Sci. Technol.

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The placenta is pivotal for fetal development and maternal–fetal transfer of many substances, including per- and polyfluoroalkyl substances (PFASs). However, the intraplacental distribution of PFASs and their effects on placental vascular function remain unclear. In this study, 302 tetrads of matched subchorionic placenta (fetal-side), parabasal placenta (maternal-side), cord serum, and maternal serum samples were collected from Guangzhou, China. Eighteen emerging and legacy PFASs and five placental vascular biomarkers were measured. Results showed that higher levels of perfluorooctanoic (PFOA), perfluorooctane sulfonic acid (PFOS), and chlorinated polyfluorinated ether sulfonic acids (Cl-PFESAs) were detected in subchorionic placenta compared to parabasal placenta. There were significant associations of PFASs in the subchorionic placenta, but not in the serum, with placental vascular biomarkers (up to 32.5%) and lower birth size. Birth weight was negatively associated with PFOA (β: −103.8, 95% CI: −186.3 and −21.32) and 6:2 Cl-PFESA (β: −80.04, 95% CI: −139.5 and −20.61), primarily in subchorionic placenta. Mediation effects of altered placental angiopoietin-2 and vascular endothelial growth factor receptor-2 were evidenced on associations of adverse birth outcomes with intraplacental PFOS and 8:2 Cl-PFESA, explaining 9.5%–32.5% of the total effect. To the best of our knowledge, this study is the first to report on differential intraplacental distribution of PFASs and placental vascular effects mediating adverse birth outcomes and provides novel insights into the placental plate-specific measurement in PFAS-associated health risk assessment.

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“…Methods for this cohort have been published. 16,17 Adults without known cardiovascular disease across the glycemic spectrum (with diabetes, glycated hemoglobin ≥6.5%, prediabetes, glycated hemoglobin 5.7%–6.4%, or normal glucose control) in the 6 months before enrollment were recruited from outpatient offices for a study of environmental exposures on noninvasive vascular function. Inclusion criteria included age 18 years; no prior cardiovascular, cerebrovascular, or peripheral arterial disease (PAD) and no active tobacco smoking in the past year.…”

Section: Methodsmentioning

confidence: 99%

Platelet RNA Biomarker of Ticagrelor-Responsive Genes Is Associated With Platelet Function and Cardiovascular Events

Myers,

Ortel,

Waldrop

et al. 2024

ATVB

Self Cite

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Background: Identifying patients with the optimal risk:benefit for ticagrelor is challenging. The aim was to identify ticagrelor-responsive platelet transcripts as biomarkers of platelet function and cardiovascular risk. Methods: Healthy volunteers (n=58, discovery; n=49, validation) were exposed to 4 weeks of ticagrelor with platelet RNA data, platelet function, and self-reported bleeding measured pre-/post-ticagrelor. RNA sequencing was used to discover platelet genes affected by ticagrelor, and a subset of the most informative was summarized into a composite score and tested for validation. This score was further analyzed (1) in CD34+ megakaryocytes exposed to an P2Y12 inhibitor in vitro, (2) with baseline platelet function in healthy controls, (3) in peripheral artery disease patients (n=139) versus patient controls (n=30) without atherosclerosis, and (4) in patients with peripheral artery disease for correlation with atherosclerosis severity and risk of incident major adverse cardiovascular and limb events. Results: Ticagrelor exposure differentially expressed 3409 platelet transcripts. Of these, 111 were prioritized to calculate a Ticagrelor Exposure Signature score, which ticagrelor reproducibly increased in discovery and validation cohorts. Ticagrelor’s effects on platelets transcripts positively correlated with effects of P2Y12 inhibition in primary megakaryocytes. In healthy controls, higher baseline scores correlated with lower baseline platelet function and with minor bleeding while receiving ticagrelor. In patients, lower scores independently associated with both the presence and extent of atherosclerosis and incident ischemic events. Conclusions: Ticagrelor-responsive platelet transcripts are a biomarker for platelet function and cardiovascular risk and may have clinical utility for selecting patients with optimal risk:benefit for ticagrelor use.

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Vascular endothelium as a target for perfluroalkyl substances (PFAs)

Cited by 6 publications

References 17 publications

Per‐ and polyfluoroalkyl substances and cardiometabolic diseases: A review

Per‐ and polyfluoroalkyl substances and cardiometabolic diseases: A review

Unveiling Distribution of Per- and Polyfluoroalkyl Substances in Matched Placenta-Serum Tetrads: Novel Implications for Birth Outcome Mediated by Placental Vascular Disruption

Platelet RNA Biomarker of Ticagrelor-Responsive Genes Is Associated With Platelet Function and Cardiovascular Events

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