Pulmonary phthalate exposure and asthma - is PPAR a plausible mechanistic link?

Due to their extensive use as plasticisers in numerous consumer products, phthalates have become ubiquitous environmental contaminants. An increasing number of epidemiological studies suggest that exposure to phthalates may be associated with worsening or development of airway diseases. Peroxisome Proliferation Activated Receptors (PPAR)s, identified as important targets for phthalates in early studies in rodent liver, have been suggested as a possible mechanistic link. In this review we discuss the likelihood of an involvement of PPARs in asthma development and exacerbation due to pulmonary phthalate exposure. First, we go through the literature on indoor air levels of phthalates and pulmonary phthalate kinetics. These data are then used to estimate the pulmonary phthalate levels due to inhalation exposure. Secondly, the literature on phthalate-induced activation or modulation of PPARs is summarized. Based on these data, we discuss whether pulmonary phthalate exposure is likely to cause PPAR activation, and if this is a plausible mechanism for adverse effects of phthalates in the lung. It is concluded that the pulmonary concentrations of some phthalates may be sufficient to cause a direct activation of PPARs. Since PPARs mainly mediate anti-inflammatory effects in the lungs, a direct activation is not a likely molecular mechanism for adverse effects of phthalates. However, possible modulatory effects of phthalates on PPARs deserve further investigation, including partial antagonist effects and/or cross talk with other signalling pathways. Moreover other mechanisms, including interactions between phthalates and other receptors, could also contribute to possible adverse pulmonary effects of phthalates

Changes in life expectancy and disease burden in Norway, 1990–2019: an analysis of the Global Burden of Disease Study 2019

Bill & Melinda Gates FoundationpublishedVersio

Phthalate exposure and allergic diseases: Review of epidemiological and experimental evidence

Phthalates are among the most ubiquitous environmental contaminants and endocrine-disrupting chemicals. Exposure to phthalates and related health effects have been extensively studied over the past four decades. An association between phthalate exposure and allergic diseases has been suggested, although the literature is far from conclusive. This article reviews and evaluates epidemiological (n = 43), animal (n = 49), and cell culture studies (n = 42), published until the end of 2019, on phthalates and allergic diseases, such as asthma, rhinoconjunctivitis, and eczema. In contrast to earlier reviews, emphasis is placed on experimental studies that use concentrations with relevance for human exposure. Epidemiological studies provide support for associations between phthalate exposures and airway, nasal, ocular, and dermal allergic disease outcomes, although the reported significant associations tend to be weak and demonstrate inconsistencies for any given phthalate. Rodent studies support that phthalates may act as adjuvants at levels likely to be relevant for environmental exposures, inducing respiratory and inflammatory effects in the presence of an allergen. Cell culture studies demonstrate that phthalates may alter the functionality of innate and adaptive immune cells. However, due to limitations of the applied exposure methods and models in experimental studies, including the diversity of phthalates, exposure routes, and allergic diseases considered, the support provided to the epidemiological findings is fragmented. Nevertheless, the current evidence points in the direction of concern. Further research is warranted to identify the most critical windows of exposure, the importance of exposure pathways, interactions with social factors, and the effects of co-exposure to phthalates and other environmental contaminants

Phthalate exposure and allergic diseases: Review of epidemiological and experimental evidence

Phthalates are among the most ubiquitous environmental contaminants and endocrine-disrupting chemicals. Exposure to phthalates and related health effects have been extensively studied over the past four decades. An association between phthalate exposure and allergic diseases has been suggested, although the literature is far from conclusive. This article reviews and evaluates epidemiological (n = 43), animal (n = 49), and cell culture studies (n = 42), published until the end of 2019, on phthalates and allergic diseases, such as asthma, rhinoconjunctivitis, and eczema. In contrast to earlier reviews, emphasis is placed on experimental studies that use concentrations with relevance for human exposure. Epidemiological studies provide support for associations between phthalate exposures and airway, nasal, ocular, and dermal allergic disease outcomes, although the reported significant associations tend to be weak and demonstrate inconsistencies for any given phthalate. Rodent studies support that phthalates may act as adjuvants at levels likely to be relevant for environmental exposures, inducing respiratory and inflammatory effects in the presence of an allergen. Cell culture studies demonstrate that phthalates may alter the functionality of innate and adaptive immune cells. However, due to limitations of the applied exposure methods and models in experimental studies, including the diversity of phthalates, exposure routes, and allergic diseases considered, the support provided to the epidemiological findings is fragmented. Nevertheless, the current evidence points in the direction of concern. Further research is warranted to identify the most critical windows of exposure, the importance of exposure pathways, interactions with social factors, and the effects of co-exposure to phthalates and other environmental contaminants

Isolating and culturing of sputum macrophages: A potential ex vivo/in vitro model

Purpose: This paper aimed to test whether induced sputum samples acquired from human volunteers could be used to isolate and culture airway macrophages for in vitro exposures. This was assessed in terms of the culturing success rate, culture purity, viability and responsiveness of cultured cells. Materials and methods: The isolation and culturing procedure was performed over three days. On Day 1, induced sputum samples were obtained, processed and seeded in culture wells. Differential cell counts and viability tests were performed to allow for calculation of viable macrophage numbers and appropriate sample dilution. After a 1 h rest, seeded wells were washed to remove non-adherent cells, resulting in macrophage isolation. Then, cells rested overnight (Day 1–Day 2), before in vitro exposure for 2–24 h (Day 2–Day 3). The criteria for progressing into the culturing procedure was cell viability >40% and total cell number >106. Successful culturing was evaluated based on cell attachment (N = 40). Culture purity by differential cell analysis and viability was monitored during culturing (N = 4–8). Macrophage responsivity was assessed by measurement of inflammatory cytokine gene expression (N = 4) and cytokine levels (N = 6) following in vitro exposure to lipopolysaccharide (LPS) (2–24 h) and live bacteria (S. aureus) (4h). Results: Overall, 88% (35/40) of the samples acquired were suitable for isolation, and 80% (32/40) were successfully progressed through the 2–3 day culturing protocol. Macrophage purity (88%) and viability (85%) were adequate. Moreover, cultured macrophages were responsive to in vitro stimulation with LPS and viable S. aureus showing positive mRNA responses for TNFα, IL-1β and IL-8 and release of IL-1β, respectively. Conclusion: Sputum macrophage isolation by plate adherence and subsequent culturing of sputum macrophages was successfully performed and represents a promising in vitro model for examination of airway macrophage behavior