In a recent study of 198 Swedish children with persistent allergic symptoms and 202 controls without such symptoms, we reported associations between the symptoms and the concentrations of n-butyl benzyl phthalate (BBzP) and di(2-ethylhexyl) phthalate (DEHP) in dust taken from the childrens' bedrooms. In the present study we examined associations between the concentrations of different phthalate esters in the dust from these bedrooms and various characteristics of the home. The study focused on BBzP and DEHP because these were the phthalates associated with health complaints. Associations have been examined using parametric and nonparametric tests as well as multiple logistic regression. For both BBzP and DEHP, we found associations between their dust concentrations and the amount of polyvinyl chloride (PVC) used as flooring and wall material in the home. Furthermore, high concentrations of BBzP (above median) were associated with self-reported water leakage in the home, and high concentrations of DEHP were associated with buildings constructed before 1960. Other associations, as well as absence of associations, are reported. Both BBzP and DEHP were found in buildings with neither PVC flooring nor wall covering, consistent with the numerous additional plasticized materials that are anticipated to be present in a typical home. The building characteristics examined in this study cannot serve as complete proxies for these quite varied sources. However, the associations reported here can help identify homes where phthalate concentrations are likely to be elevated and can aid in developing mitigation strategies.

Phthalates in indoor dust and their association with building characteristics

Upon antigen recognition, naive T cells undergo rapid expansion and activation. The energy requirements for this expansion are formidable, and T-cell activation is accompanied by dramatic changes in cellular metabolism. Furthermore, the outcome of antigen engagement is guided by multiple cues derived from the immune microenvironment. Mammalian target of rapamycin (mTOR) is emerging as a central integrator of these signals playing a critical role in driving T-cell differentiation and function. Indeed, multiple metabolic programs are controlled by mTOR signaling. In this review, we discuss the role of mTOR in regulating metabolism and how these pathways intersect with the ability of mTOR to integrate cues that guide the outcome of T-cell receptor engagement.

/pdf/mtor-metabolism-and-the-regulation-of-t-cell-differentiation-3gaeyz96xp.pdf

mTOR, metabolism, and the regulation of T-cell differentiation and function

In the developed parts of the world, people spend ≥ 90% of their life indoors (Brasche and Bischof 2005), which implies that indoor environmental conditions are important for people’s health. Indoors, pollutants in dust and air are often generated from sources such as environmental tobacco smoke, building materials, furniture, cleaning and hygienic products, air fresheners, computers, printers, cooking and other indoor activities, and from people themselves.

Over the last few decades, asthma and allergies have increased all over the world [Asher et al. 2006; ISAAC (International Study of Asthma and Allergy in Childhood) Steering Committee 1998; World Health Organization 2003]. The causes of the increase in asthma and allergies are still unknown. Genetic changes are not believed to be important because the time interval (30–50 years) for the increase in allergies is far too short. Instead, environmental changes are suspected as possible causes. Several hypotheses have been put forward. Much interest has been focused on the so called “hygiene hypothesis”—that a lack of microbial exposure during critical periods in infancy increases the risk of allergies (Strachan 1989). However, it seems likely that this hypothesis may not be the sole cause, and that other hypotheses are required (Platts-Mills et al. 2005). One such hypothesis is that the increase in allergies is attributable to new adjuvant factors: exposure to environmental pollutants such as endocrine disruptors (e.g., phthalate esters) which may act as modulators of the immune system and induce an allergic response (Chalubinski and Kowalski 2006).

One of the main sources for phthalate esters indoors is the plasticized polyvinyl chloride (PVC) materials (Bornehag et al. 2005a) that are used in floor and wall covering materials, shower curtains, adhesives, synthetic leather, toys, cosmetics, and many other consumer products. Phthalates are constantly being emitted to the air and indoor dust because they are not chemically bound to the PVC structure (Wormuth et al. 2006).

The presence of phthalates in indoor dust (Becker et al. 2004; Bornehag et al. 2004; Butte et al. 2001; Clausen et al. 2003; Fromme et al. 2004; Kersten and Reich 2003; Oie et al. 1997; Pohner et al. 1997; Rudel et al. 2003) and in indoor air (Adibi et al. 2003; Fromme et al. 2004; Rudel et al. 2003) is well documented. In the literature, the predominant phthalate described in indoor dust is di(2-ethylhexyl) phthalate (DEHP), typically observed in a concentration range of 0.01–10 mg/g dust, followed by butyl benzyl phthalate (BBzP) in concentrations up to 1.3 mg/g dust. The phthalate concentration in indoor air is usually lower than the concentration in dust, and the predominant phthalates are diethyl phthalate (DEP) and di-n-butyl phthalate (DnBP) in the concentration range of 0.05–5 μg/m3. Human exposure to phthalates has been studied mainly by monitoring concentrations of metabolites in body fluids such as urine or blood (Adibi et al. 2003; Becker et al. 2004; Blount et al. 2000; Calafat et al. 2004; Green et al. 2005; Koch et al. 2003, 2005). The results have shown that people are exposed to multiple phthalates and that children often are more exposed than adults (Calafat et al. 2004; Green et al. 2005; Koch et al. 2005).

There is some epidemiologic evidence for an association between the concentration of phthalates in indoor dust and/or the occurrence indoors of plasticized products such as PVC and allergic symptoms in the airways (e.g., asthma), nose, and skin. Jaakkola et al. (1999) found that the total area of PVC surface materials in homes was associated with the development of bronchial obstruction in small children in Norway. In a study from Finland (Jaakkola et al. 2000), lower respiratory tract symptoms in children such as persistent wheezing, cough, and phlegm were associated with the presence of plastic wall materials, whereas upper respiratory tract symptoms were not. Also, the relative risk estimated for pneumonia, bronchitis, and otitis media among children was slightly increased in the presence of plastic wall materials (Jaakkola et al. 2000). In a population-based incident case–control study among adults (21–63 years of age), Jaakkola et al. (2006) found that the risk of asthma was significantly related to the presence of plastic wall materials at work.

In the first phase of the Swedish DBH (Dampness in Buildings and Health) study it was found that PVC as flooring material in combination with moisture problems in the floors was associated with asthma among children 1–6 years of age (Bornehag et al. 2005b). Furthermore, in the second phase of the DBH study a strong dose–response relationship was found between asthma among children and DEHP concentration in indoor dust and between eczema and rhinitis and BBzP (Bornehag et al. 2004). Oie et al. (1997) provided evidence that inhalation exposure to DEHP as aerosols adsorbed to particulate matter is even more important than vapor phase exposure. They discussed possible mechanisms for respiratory effects by inhalation exposure and concluded that deposition of DEHP in the lungs may increase the risk of inflammation in the airways, a characteristic feature of asthma.

The results from toxicologic studies are conflicting. Lee et al. (2004) reported that DEHP and di-isononyl phthalate (DINP) enhance allergic responses by enhancement of interleukin (IL)-4 production in CD4+ T cells via stimulation of NF-AT (nuclear factor of activated T cells)–binding activity. Glue et al. (2005) investigated the effect of phthalates to modulate the release of histamine from isolated basophils. None of the phthalates tested was found to induce histamine release per se, but higher histamine release was observed when the cells were first treated with phthalates and then exposed to an allergen. Recently, Larsen et al. (2007) reported that long-term inhalation of DEHP together with an allergen resulted in allergy sensitization only in concentrations of 13 mg/m3. These authors concluded that DEHP, at realistic concentrations, does not cause adjuvant effects nor allergic lung inflammation in humans. In a recent review, Nielsen et al. (2007) concluded that results from animal and epidemiologic studies are discordant.

This study (The ALLHOME study) was initiated in Bulgaria in 2004. The overall aim of the study was to map housing conditions and indoor exposures in Bulgaria and to investigate the role of such factors for allergies and asthma among small children (Naydenov 2007; Naydenov et al. 2005).

Our main aim in the present article is to investigate associations between persistent allergic symptoms in preschool Bulgarian children and the concentrations of different phthalate esters in dust collected from the children’s bedrooms.

/pdf/the-association-between-phthalates-in-dust-and-allergic-3samw5r242.pdf

The Association between Phthalates in Dust and Allergic Diseases among Bulgarian Children

During the last decades more than 100 000 new chemicals have been introduced to the environment. Many of these new chemicals and many common consumer products that include these have been shown to be toxic in animal studies and an increasing body of evidence suggests that they are also impacting human health. Among the suspect chemicals, the endocrine disrupting chemicals (EDCs) are of particular concern. One such chemical group is the phthalates, used in soft poly vinyl chloride (PVC) material and in a huge number of consumer products. During the same period of time that the prevalence of these modern chemicals has increased, there has been a remarkable increase in several chronic illnesses, including asthma and allergy in children. In this article we outline the scientific knowledge on phthalate exposure for asthma and airway diseases in children by examining epidemiological and experimental peer review data for potential explanatory mechanisms. Epidemiological data point to a possible correlation between phthalate exposure and asthma and airway diseases in children. Experimental studies present support for an adjuvant effect on basic mechanisms in allergic sensitization by several phthalates. Despite variations in the experimental design and reported result in the individual studies, a majority of published reports have identified adjuvant effects on Th2 differentiation, production of Th2 cytokines and enhanced levels of Th2 promoted immunoglobulins (mainly IgG1 but also IgE) in mice. A limited amount of data do also suggest phthalate-induced enhancement of mast cell degranulation and eosinophilic infiltration which are important parts in the early inflammation phase. Thus, some of the early key mechanisms in the pathology of allergic asthma could possibly be targeted by phthalate exposure. But the important questions of clinical relevance of real life exposure and identification of molecular targets that can explain interactions largely remain to be answered.

https://onlinelibrary.wiley.com:443/doi/pdf/10.1111/j.1365-2605.2009.01023.x

Phthalate exposure and asthma in children

Infants of smokers have much higher rates of respiratory infection, asthma and airway disease. The current study assessed the effects of maternal smoking in pregnancy on neonatal toll-like-receptor (TLR)-mediated immune responses as a possible contributing factor to the elevated rates of respiratory illness. In a prospective birth cohort, the cord blood immune responses of neonates of smoking and nonsmoking mothers were compared. Maternal and cord serum cotinine were measured to confirm the level of cigarette smoke exposure. Neonatal cytokine responses were assessed to optimal doses of TLR2, TLR3, TLR4 and TLR9 ligands. Cotinine levels confirmed maternal reporting of cigarette smoking in pregnancy, with significantly higher cotinine levels in maternal and cord blood compared with the nonsmoking group. Infants of smoking mothers showed significantly attenuated innate TLR-mediated responses compared with infants of nonsmokers. The current findings indicate that in addition to effects on developing airways, maternal smoking also has significant immunological effects in pregnancy, which could contribute to the well recognised, subsequent increased risk of respiratory infections and asthma. These effects appear to be mediated through effects on toll-like receptor-mediated innate response pathways, which also promote regulatory pathways in the inhibition of allergic immune responses in the postnatal period, suggesting that other environmental interactions are highly relevant to the "hygiene hypothesis".

https://erj.ersjournals.com/content/erj/28/4/721.full.pdf

Maternal smoking is associated with impaired neonatal toll-like-receptor-mediated immune responses

Background: Diethylhexyl phthalate (DEHP) and diisononyl phthalate (DINP), two commonly used plasticizers in flexible polyvinylchloride formulations, have potentially adverse effects on human health. However, the influence of these diphthalates on allergic responses remains unclear. In this study we examined the effects of DEHP and DINP on IL-4 production in CD4+ T cells and the level of IgE in sera, critical hallmarks associated with allergic diseases. Methods: Mouse T cells were exposed to two diphthalates in vitro and in vivo. The levels of IL-4 and IgE were determined by ELISA, and the degree of NF-AT activation was determined by IL-4 gene promoter assay and electrophoretic mobility shift assay. Results and Discussion: Both DEHP and DINP significantly enhanced IL-4 production in activated CD4+ T cells in a concentration-dependent manner. Treatment with DEHP or DINP in vivo resulted in a significant increase of IL-4 production in CD4+ T cells and of IgE levels in sera. Furthermore, DEHP and DINP enhanced the activation of IL-4 gene promoter in EL4 T cells and the enhancing effect mapped to a region in the IL-4 promoter containing binding sites for a transcription factor, NF-AT. The activation of T cells resulted in markedly enhanced binding activities to the NF-AT site, which significantly increased upon addition of DEHP or DINP, indicating that NF-AT was involved in the enhancing effect of DEHP and DINP on IL-4 production. These findings suggest that both DEHP and DINP enhance allergic responses by enhancement of IL-4 production in CD4+ T cells via stimulation of NF-AT-binding activity.

Enhancement of interleukin-4 production in activated CD4+ T cells by diphthalate plasticizers via increased NF-AT binding activity.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been implicated in the regulation of multiple inflammatory processes. However, little is known of PPAR-gamma in the regulation of interleukin (IL)-4 expression in T cells. In this study, the effects of PPAR-gamma ligands on production of IL-4, a pro-inflammatory cytokine associated with the pathophysiology of allergic diseases, were investigated. 15-Deoxy-Delta12,14 prostaglandin J2 (15d-PGJ2) and ciglitazone, two representative PPAR-gamma ligands, significantly inhibited IL-4 production in both antigen-stimulated primary CD4+ T cells and the phorbol 12-myristate 13-acetate (PMA)/ionomycin-activated EL-4 T cell line. 15d-PGJ2 and ciglitazone inhibited the activation of IL-4 gene promoter in EL-4 T cells transiently transfected with IL-4 promoter/reporter constructs, and the repressive effect mapped to a region in the IL-4 promoter containing binding sites for nuclear factor of activated T cells (NF-AT). The activation of T cells by PMA/ionomycin resulted in a marked enhancement of the binding activities to the NF-AT site that was significantly inhibited by the addition of PPAR-gamma ligands. In cotransfected EL-4 T cells, PPAR-gamma also inhibited the activation of the IL-4 promoter at multiple NF-AT sites in a ligand-dependent manner. NF-ATc1 bound PPAR-gamma both in vivo and in vitro, and the interaction interfaces involved the Rel similarity domain of NF-ATc1. In cotransfections of HeLa cells, PPAR-gamma inhibited the NF-ATc1 transactivation in a ligand-dependent manner. Coexpression of p300 or AP-1 relieved the PPAR-gamma ligand-mediated inhibition of the NF-AT transactivation. From these results, we propose that PPAR-gamma ligand-mediated suppression of IL-4 production in CD4+ T cells may involve both inhibition of the NFAT-DNA interactions and competitive recruitment of transcription integrators between NF-AT and PPAR-gamma.

Inhibition of Interleukin-4 Production in CD4+ T Cells by Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) Ligands: Involvement of Physical Association between PPAR-γ and the Nuclear Factor of Activated T Cells Transcription Factor

Inhibition of interleukin-12 production in mouse macrophages by hydroquinone, a reactive metabolite of benzene, via suppression of nuclear factor-κB binding activity

Bok Yun Kang

Papers

Enhancement of interleukin-4 production in activated CD4+ T cells by diphthalate plasticizers via increased NF-AT binding activity.

Inhibition of Interleukin-4 Production in CD4+ T Cells by Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) Ligands: Involvement of Physical Association between PPAR-γ and the Nuclear Factor of Activated T Cells Transcription Factor

Inhibition of interleukin-12 production in mouse macrophages by hydroquinone, a reactive metabolite of benzene, via suppression of nuclear factor-κB binding activity