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Per- and polyfluoroalkyl substances (PFAS) are anthropogenic organofluorine compounds that persist indefinitely in the environment and bioaccumulate throughout all trophic levels. Biomonitoring efforts have detected multiple PFAS in the serum of most people. Immune suppression has been among the most consistent effects of exposure to PFAS. PFAS often co-occur as mixtures in the environment, however, few studies have examined immunosuppression of PFAS mixtures or determined whether PFAS exposure affects immune function in the context of infection. In this study, mixtures containing two or four different PFAS and a mouse model of infection with influenza A virus (IAV) were used to assess immunotoxicity of PFAS mixtures. PFAS were administered via the drinking water as either a binary mixture of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) or quaternary mixture of PFOS, PFOA, perfluorohexane sulfonate (PFHxS), and perfluorononanoic acid (PFNA). The results indicated that the binary mixture affected the T-cell response, while the quaternary mixture affected the B-cell response to infection. These findings indicate that the immunomodulatory effects of PFAS mixtures are not simply additive, and that the sensitivity of immune responses to PFAS varies by cell type and mixture. The study also demonstrates the importance of studying adverse health effects of PFAS mixtures.

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Developmental exposures can influence life-long health; yet, counteracting negative consequences is challenging due to poor understanding of cellular mechanisms. The aryl hydrocarbon receptor (AHR) binds many small molecules, including numerous pollutants. Developmental exposure to the signature environmental AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) significantly dampens adaptive immune responses to influenza A virus (IAV) in adult offspring. CD8+ cytotoxic T lymphocytes (CTL) are crucial for successful infection resolution, which depends on the number generated and the complexity of their functionality. Prior studies showed developmental AHR activation significantly reduced the number of virus-specific CD8+ T cells, but impact on their functions is less clear. Other studies showed developmental exposure was associated with differences in DNA methylation in CD8+ T cells. Yet, empirical evidence that differences in DNA methylation are causally related to altered CD8+ T cell function is lacking. The two objectives were to ascertain whether developmental AHR activation affects CTL function, and whether differences in methylation contribute to reduced CD8+ T cell responses to infection. Developmental AHR triggering significantly reduced CTL polyfunctionality, and modified the transcriptional program of CD8+ T cells. S-adenosylmethionine (SAM), which increases DNA methylation, but not Zebularine, which diminishes DNA methylation, restored polyfunctionality and boosted the number of virus-specific CD8+ T cells. These findings suggest that diminished methylation, initiated by developmental exposure to an AHR-binding chemical, contributes to durable changes in antiviral CD8+ CTL functions later in life. Thus, deleterious consequence of development exposure to environmental chemicals are not permanently fixed, opening the door for interventional strategies to improve health.

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Epidemiological studies associate biomass smoke with an increased risk for respiratory infections in children and adults in the developing world, with 500,000 premature deaths each year attributed to biomass smoke-related acute respiratory infections including infections caused by respiratory viruses. Animal dung is a biomass fuel of particular concern because it generates more toxic compounds per amount burned than wood, and is a fuel of last resort for the poorest households. Currently, there is little biological evidence on the effects of dung biomass smoke exposure on immune responses to respiratory viral infections. Here, we investigated the impact of dung biomass exposure on respiratory infection using a mouse model of dung biomass smoke and cultured primary human small airway epithelial cells (SAECs). Mice infected with influenza A virus (IAV) after dung biomass smoke exposure had increased mortality, lung inflammation and virus mRNA levels, and suppressed expression of innate anti-viral mediators compared to air exposed mice. Importantly, there was still significant tissue inflammation 14 days after infection in dung biomass smoke-exposed mice even after inflammation had resolved in air-exposed mice. Dung biomass smoke exposure also suppressed the production of anti-viral cytokines and interferons in cultured SAECs treated with poly(I:C) or IAV. This study shows that dung biomass smoke exposure impairs the immune response to respiratory viruses and contributes to biomass smoke-related susceptibility to respiratory viral infections, likely due to a failure to resolve the inflammatory effects of biomass smoke exposure.

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BACKGROUND: Early life environmental exposures can have lasting effects on the function of the immune system and contribute to disease later in life. Epidemiological studies have linked early life exposure to xenobiotics that bind the aryl hydrocarbon receptor (AhR) with dysregulated immune responses later in life. Among the immune cells influenced by developmental activation of the AhR are CD4+ T cells. Yet, the underlying affected cellular pathways via which activating the AhR early in life causes the responses of CD4+ T cells to remain affected into adulthood remain unclear. OBJECTIVE: Our goal was to identify cellular mechanisms that drive impaired CD4+ T-cell responses later in life following maternal exposure to an exogenous AhR ligand. METHODS: C57BL/6 mice were vertically exposed to the prototype AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), throughout gestation and early postnatal life. The transcriptome and DNA methylation patterns were evaluated in CD4+ T cells isolated from naïve and influenza A virus (IAV)-infected adult mice that were developmentally exposed to TCDD or vehicle control. We then assessed the influence of DNA methylation-altering drug therapies on the response of CD4+ T cells from developmentally exposed mice to infection. RESULTS: Gene and protein expression showed that developmental AhR activation reduced CD4+ T-cell expansion and effector functions during IAV infection later in life. Furthermore, whole-genome bisulfite sequencing analyses revealed that developmental AhR activation durably programed DNA methylation patterns across the CD4+ T-cell genome. Treatment of developmentally exposed offspring with DNA methylation-altering drugs alleviated some, but not all, of the impaired CD4+ T-cell responses. DISCUSSION: Taken together, these results indicate that skewed DNA methylation is one of the mechanisms by which early life exposures can durably change the function of T cells in mice. Furthermore, treatment with DNA methylation-altering drugs after the exposure restored some aspects of CD4+ T-cell functional responsiveness. https://doi.org/10.1289/EHP7699.

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Recent studies have linked health fates of children to environmental exposures of their great grandparents. However, few studies have considered whether ancestral exposures influence immune function across generations. Here, we report transgenerational inheritance of altered T cell responses resulting from maternal (F0) exposure to the aryl hydrocarbon receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Since F0 exposure to TCDD has been linked to transgenerational transmission of reproductive problems, we asked whether maternal TCDD exposure also caused transgenerational changes in immune function. F0 exposure caused transgenerational effects on the CD8+ T cell response to influenza virus infection in females but not in males. Outcrosses showed changes were passed through both parental lineages. These data demonstrate that F0 exposure to an aryl hydrocarbon receptor (AHR) agonist causes durable changes to immune responses that can affect subsequent generations. This has broad implications for understanding how the environment of prior generations shapes susceptibility to pathogens and antiviral immunity in later generations.

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Early life environmental exposures drive lasting changes to the function of the immune system and can contribute to disease later in life. One of the ways environmental factors act is through cellular receptors. The aryl hydrocarbon receptor (AHR) is expressed by immune cells and binds numerous xenobiotics. Early life exposure to chemicals that bind the AHR impairs CD4+ T cell responses to influenza A virus (IAV) infection in adulthood. However, the cellular mechanisms that underlie these durable changes remain poorly defined. Transcriptomic profiling of sorted CD4+ T cells identified changes in genes involved in proliferation, differentiation, and metabolic pathways were associated with triggering AHR during development. Functional bioassays confirmed that CD4+ T cells from infected developmentally exposed offspring exhibit reduced proliferation, differentiation, and cellular metabolism. Thus, developmental AHR activation shapes T cell responsive capacity later in life by affecting integrated cellular pathways, which collectively alter responses later in life. Given that coordinated shifts in T cell metabolism are essential for T cell responses to numerous challenges, and that humans are constantly exposed to many different types of AHR ligands, this has far-reaching implications for how AHR signaling, particularly during development, durably influences T cell mediated immune responses across the lifespan.

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Successfully fighting infection requires a properly tuned immune system. Recent epidemiological studies link exposure to pollutants that bind the aryl hydrocarbon receptor (AHR) during development with poorer immune responses later in life. Yet, how developmental triggering of AHR durably alters immune cell function remains unknown. Using a mouse model, we show that developmental activation of AHR leads to long-lasting reduction in the response of CD8(+) T cells during influenza virus infection, cells critical for resolving primary infection. Combining genome-wide approaches, we demonstrate that developmental activation alters DNA methylation and gene expression patterns in isolated CD8(+) T cells prior to and during infection. Altered transcriptional profiles in CD8(+) T cells from developmentally exposed mice reflect changes in pathways involved in proliferation and immunoregulation, with an overall pattern that bears hallmarks of T cell exhaustion. Developmental exposure also changed DNA methylation across the genome, but differences were most pronounced following infection, where we observed inverse correlation between promoter methylation and gene expression. This points to altered regulation of DNA methylation as one mechanism by which AHR causes durable changes in T cell function. Discovering that distinct gene sets and pathways were differentially changed in developmentally exposed mice prior to and after infection further reveals that the process of CD8(+) T cell activation is rendered fundamentally different by early life AHR signaling. These findings reveal a novel role for AHR in the developing immune system: regulating DNA methylation and gene expression as T cells respond to infection later in life.

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