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Exposure to a mixture of per-and polyfluoroalkyl substances modulates pulmonary expression of ACE2 and circulating hormones and cytokines.
Yang, Zhao; Roth, Katherine; Ding, Jiahui; Kassotis, Christopher D; Mor, Gil; Petriello, Michael C.
  • Yang Z; Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA.
  • Roth K; Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA.
  • Ding J; C.S Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA.
  • Kassotis CD; Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA; Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48202, USA.
  • Mor G; C.S Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA.
  • Petriello MC; Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA; Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48202, USA. Electronic address: Michael.petriello@wayne.edu.
Toxicol Appl Pharmacol ; 456: 116284, 2022 Dec 01.
Article in English | MEDLINE | ID: covidwho-2086745
ABSTRACT
Genetic and environmental factors impact on the interindividual variability of susceptibility to communicable and non-communicable diseases. A class of ubiquitous chemicals, Per- and polyfluoroalkyl substances (PFAS) have been linked in epidemiological studies to immunosuppression and increased susceptibility to viral infections, but possible mechanisms are not well elucidated. To begin to gain insight into the role of PFAS in susceptibility to one such viral infection, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), male and female C57BL/6 J mice were exposed to control water or a mixture of 5 PFAS (PFOS, PFOA, PFNA, PFHxS, Genx) for 12 weeks and lungs were isolated for examination of expression of SARS-CoV-2-related receptors Angiotensin-Converting Enzyme 2 (ACE2) and others. Secondary analyses included circulating hormones and cytokines which have been shown to directly or indirectly impact on ACE2 expression and severity of viral infections. Changes in mRNA and protein expression were analyzed by RT-qPCR and western blotting and circulating hormones and cytokines were determined by ELISA and MESO QuickPlex. The PFAS mixture decreased Ace2 mRNA 2.5-fold in male mice (p < 0.0001), with no significant change observed in females. In addition, TMPRSS2, ANPEP, ENPEP and DPP4 (other genes implicated in COVID-19 infection) were modulated due to PFAS. Plasma testosterone, but not estrogen were strikingly decreased due to PFAS which corresponded to PFAS-mediated repression of 4 representative pulmonary AR target genes; hemoglobin, beta adult major chain (Hbb-b1), Ferrochelatase (Fech), Collagen Type XIV Alpha 1 Chain (Col14a1), 5'-Aminolevulinate Synthase 2 (Alas2). Finally, PFAS modulated circulating pro and anti-inflammatory mediators including IFN-γ (downregulated 3.0-fold in females; p = 0.0301, 2.1-fold in males; p = 0.0418) and IL-6 (upregulated 5.6-fold in males; p = 0.030, no change in females). In conclusion, our data indicate long term exposure to a PFAS mixture impacts mechanisms related to expression of ACE2 in the lung. This work provides a mechanistic rationale for important future studies of PFAS exposure and subsequent viral infection.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Fluorocarbons / COVID-19 Type of study: Observational study / Prognostic study Limits: Animals Language: English Journal: Toxicol Appl Pharmacol Year: 2022 Document Type: Article Affiliation country: J.taap.2022.116284

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Fluorocarbons / COVID-19 Type of study: Observational study / Prognostic study Limits: Animals Language: English Journal: Toxicol Appl Pharmacol Year: 2022 Document Type: Article Affiliation country: J.taap.2022.116284