Abstract
Exposure to environmental hormones such as di(2-ethylhexyl) phthalate (DEHP) has become a critical human health issue globally. This study aimed to investigate the correlations between DEHP/mono-(2-ethylhexyl) phthalate (MEHP) levels and macrophage-associated immune responses and clinical manifestations in dengue virus (DV)-infected patients. Among 89 DV-infected patients, those with DV infection-related gastrointestinal (GI) bleeding (n = 13, 15% of patients) had significantly higher DEHP exposure than those without GI bleeding (n = 76, 85% of patients), which were 114.2 ng/ml versus 52.5 ng/ml ΣDEHP in urine; p = 0.023). In an in vitro study using cultured human monocyte-derived macrophages (MDMs) to investigate the effects of MEHP, treatment increased IL-1β and TNF-α release but decreased IL-23 release, with negative correlations observed between urine ΣDEHP and serum IL-23 levels in patients. MEHP-treated MDMs had lower antiviral Th17 response induction activity in mixed T-cell response tests. The in vitro data showed that MEHP increased DV viral load and decreased IL-23 release dose-dependently, and adding IL-23 to MEHP-exposed MDMs significantly reduced the DV viral load. MEHP also suppressed IL-23 expression via the peroxisome proliferator-activated receptor-gamma (PPAR-γ) pathway. Further, the PPAR-γ antagonist GW9662 significantly reversed MEHP-induced IL-23 suppression and reduced the DV viral load. These study findings help to explain the associations between high MEHP levels and the high global burden of dengue disease.
Highlights
Dengue fever is caused by dengue virus (DV) infection mediated by a mosquito (Aedes aegypti or Aedes albopictus) bite and occurs predominantly in tropical and subtropical areas
Results of screening for mono-(2-ethylhexyl) phthalate (MEHP)-induced alterations in DV infection-associated macrophage cytokines/chemokines in cultured monocyte-derived macrophages (MDMs) revealed that MEHP increased IL-1b and TNF-a release but decreased IL-10 and IL-23 release in human MDMs (Figure 2A)
Among the 15 DV infectionassociated cytokines in patient samples (Supplementary Table S2– S6), the decreased IL-23 level was validated in DV-infected patients with higher SDEHP exposure (Figure 2B)
Summary
Dengue fever is caused by dengue virus (DV) infection mediated by a mosquito (Aedes aegypti or Aedes albopictus) bite and occurs predominantly in tropical and subtropical areas. The World Health Organization (WHO) reports that the prevalence of dengue fever has increased continuously for nearly 30 years in more than 100 countries [1]. The WHO estimates that 2.5 billion people are at risk of DV infection, and 390 million people are infected [2] Among those infected, 96 million show clinical manifestations, and 0.5 million are identified as having DHF [3]. In 2014, a severe outbreak (> 15,000 cases) of dengue fever occurred in southern Taiwan after an illegal di(2-ethylhexyl) phthalate (DEHP) food additive incident that affected a large percentage of the national population [5]. More than 120 DHF cases and nearly 20 deaths were reported at Kaohsiung Medical University Hospital. Phthalate exposure has been reported to alter macrophage functions [7] and, probably contributes to the development of an increasing number of DV-related infectious complications [8]
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