The Effects of Gene × Environment Interactions on Silver Nanoparticle Toxicity in the Respiratory System

Abstract

Silver nanoparticles (AgNP) are used in multiple applications but primarily in the manufacturing of antimicrobial products. AgNP toxicity in the respiratory system is well characterized, but few in vitro or in vivo studies have evaluated the effects of interactions between host genetic and acquired factors or gene × environment interactions (G × E) on AgNP toxicity in the respiratory system. The primary goal of this article is to review host genetic and acquired factors identified across in vitro and in vivo studies and prioritize those necessary for defining exposure limits to protect all populations. The impact of these exposures and the work being done to address the current limited protections are also discussed. Future research on G × E effects on AgNP toxicity is warranted and will assist with informing regulatory or recommended exposure limits that enforce special protections for all populations to AgNP exposures in occupational settings.

The effects of gene × environment interactions on silver nanoparticle toxicity in the respiratory system: An adverse outcome pathway

“…We previously reviewed a Scoville et al study, which “treated 25 genotypes of male mice (including A/J, BALB/cJ, and C57BL6/J), and observed genotype effects on Ag mass associated in the lungs as well as AgNP‐induced T2 lung inflammation (marked by increased pro‐inflammatory cell secretion) compared to genetically‐matched vehicle controls, with BALB/cJ and SWR/J mice being the most differentially sensitive genotypes. The authors used RNA‐seq on lungs isolated from A/J, BALB/cJ, and C57BL6/J mice and observed an inverse relationship between AgNP‐induced T2 lung inflammation and expression of E3 ubiquitin‐protein ligase NEDD4‐like ( Nedd4l ), anoctamin 6 ( Ano6 ), and E3 ubiquitin‐protein ligase RNF220 ( Rnf220 ), which may function as candidate polymorphisms for AgNP‐induced T2 lung inflammation” (Nicholas et al, 2019; Scoville et al, 2017). We described Nedd4l as “a E3 ubiquitin ligase gene involved in ubiquitin protein ligase activity” and suggested that AgNP‐induced Nedd4l downregulation “may increase amiloride‐sensitive epithelial Na + channel (ENaC) activity and T2 lung inflammation” (Nicholas et al, 2019; Scoville et al, 2017).…”

“…The authors used RNA‐seq on lungs isolated from A/J, BALB/cJ, and C57BL6/J mice and observed an inverse relationship between AgNP‐induced T2 lung inflammation and expression of E3 ubiquitin‐protein ligase NEDD4‐like ( Nedd4l ), anoctamin 6 ( Ano6 ), and E3 ubiquitin‐protein ligase RNF220 ( Rnf220 ), which may function as candidate polymorphisms for AgNP‐induced T2 lung inflammation” (Nicholas et al, 2019; Scoville et al, 2017). We described Nedd4l as “a E3 ubiquitin ligase gene involved in ubiquitin protein ligase activity” and suggested that AgNP‐induced Nedd4l downregulation “may increase amiloride‐sensitive epithelial Na + channel (ENaC) activity and T2 lung inflammation” (Nicholas et al, 2019; Scoville et al, 2017). We also described Ano6 as a “small‐conductance calcium‐activated nonselective cation channel gene involved in calcium‐dependent exposure of phosphatidylserine on the cell surface”, and posited that AgNP‐induced Ano6 downregulation “may impair ion transport, increase airway surface fluid volume and viscosity, as well as apoptosis, phagocytosis, and T2 lung inflammation and/or mast cell degranulation via the phosphatidylserine signaling pathway” (Nicholas et al, 2019; Scoville et al, 2017).…”

“…We previously reviewed multiple in vivo studies that “evaluated genotype and in vivo airway phenotype effects on AgNP toxicity in the lungs using OVA‐sensitized female BALB/cJ mice, which develop increased AHR and T2 lung inflammation than male mice or other mice genotypes” and noted that these studies “treated OVA‐sensitized, female BALB/cJ or C57BL6/J mice with AgNP of various sizes and coatings” (Nicholas et al, 2019). We also noted “limited evidence of genotype or in vivo airway phenotype effects on Ag mass associated in the lungs.…”

“…We previously reviewed multiple in vivo studies that “evaluated sex and genotype effects on AgNP toxicity in the lungs using either Brown‐Norway or Sprague‐Dawley rats” and noted that these studies “treated male Brown‐Norway or male and female Sprague‐Dawley rats with AgNP of various sizes and coatings” (Nicholas et al, 2019). We also noted “evidence of sex and genotype effects on Ag mass associated in the lungs as well as AgNP‐induced oxidative stress (marked by increased malondialdehyde [MDA] secretion [Brown‐Norway]), T2/T17 lung inflammation (marked by increased T1/T2/T17 cytokine secretion, pro‐inflammatory cell secretion, and changes in histopathology associated with lung inflammation [Brown‐Norway]), and changes in organ physiology (marked by decreased airway resistance, tissue elastance [measured by forced oscillation; Brown Norway], as well as minute and tidal volume [Sprague‐Dawley]) compared to genetically‐matched vehicle controls, with males being the more sensitive sex and Brown‐Norway rats being the more sensitive genotype” (Nicholas et al, 2019; Seiffert et al, 2015, 2016; Sung et al, 2008, 2009).…”

“…One limitation of the Jeannet et al study was “its limited dissociation of the CFTR polymorphism from its resulting in vitro airway phenotype, so therefore it was difficult to conclude as to whether AgNP toxicity was attributed either directly to the CFTR polymorphism or indirectly to its resulting in vitro airway phenotype” (Jeannet et al, 2015; Nicholas et al, 2019). However, one strength of this study was “its use of primary cells, which allowed the authors to show how this polymorphism and its resulting in vitro airway phenotype captured the in vitro impact of underlying genetics and morbidities on exposure risk and response variability” (Jeannet et al, 2015; Nicholas et al, 2019). One limitation of our previous study was its focus on a single mouse sex and two genotypes, which did not account for higher order interactions between host genetic and acquired factors.…”