Eiko Koike

Bisphenol S (BPS) is increasingly being used as an alternative for bisphenol A; however, its health effects remain unclear. We investigated the effects of oral exposure to low-dose BPS on allergic asthma. C3H/HeJ male mice were intratracheally administered with allergen (ovalbumin (OVA), 1 μg/animal) every 2 weeks from 6 to 11 weeks old. BPS was ingested by drinking water at doses equivalent to 0.04, 0.4, and 4 μg/kg/day. We then examined pulmonary inflammation, airway hyperresponsiveness, serum OVA-specific immunoglobulin (Ig) levels, Th2 cytokine/chemokine production, and mediastinal lymph node (MLN) cell activities. Compared with OVA alone, moderate-dose BPS (BPS-M) with OVA significantly enhanced pulmonary inflammation, airway hyperresponsiveness, and OVA-specific IgE and IgG1. Furthermore, interleukin (IL)-5, IL-13, IL-33, and CCL11/Eotaxin protein levels in the lungs increased. Conversely, these allergic responses were reduced in the high-dose BPS+OVA group. In MLN cells, BPS-M with OVA increased the total cell count and activated antigen-presenting cells including conventional dendritic cell subset (cDC2). After OVA restimulation, cell proliferation and Th2 cytokine production (IL-4, IL-5, and IL-13) in the culture supernatant also increased. Therefore, oral exposure to low-dose BPS may exacerbate allergic asthmatic responses by enhancing Th2-polarized responses and activating the MLN cells.

Tris (2-butoxyethyl) phosphate (TBEP) is an organophosphate flame retardant and used as a plasticizer in various household products such as plastics, floor polish, varnish, textiles, furniture, and electronic equipment. However, little is known about the effects of TBEP on the brain and behavior. We aimed to examine the effects of dietary exposure of TBEP on memory functions, their-related genes, and inflammatory molecular markers in the brain of allergic asthmatic mouse models. C3H/HeJSlc male mice were given diet containing TBEP (0.02 (TBEP-L), 0.2 (TBEP-M), or 2 (TBEP-H) μg/kg/day) and ovalbumin (OVA) intratracheally every other week from 5 to 11 weeks old. A novel object recognition test was conducted in each mouse at 11 weeks old. The hippocampi were collected to detect neurological, glia, and immunological molecular markers using the real-time RT-PCR method and immunohistochemical analyses. Mast cells and microglia were examined by toluidine blue staining and ionized calcium-binding adapter molecule (Iba)-1 immunoreactivity, respectively. Impaired discrimination ability was observed in TBEP-H-exposed mice with or without allergen. The mRNA expression levels of N-methyl-D aspartate receptor subunits Nr1 and Nr2b, inflammatory molecular markers tumor necrosis factor-α oxidative stress marker heme oxygenase 1, microglia marker Iba1, and astrocyte marker glial fibrillary acidic protein were significantly increased in TBEP-H-exposed mice with or without allergen. Microglia and mast cells activation were remarkable in TBEP-H-exposed allergic asthmatic mice. Our results indicate that chronic exposure to TBEP with or without allergen impaired object recognition ability accompanied with alteration of molecular expression of neuronal and glial markers and inflammatory markers in the hippocampus of mice. Neuron-glia-mast cells interaction may play a role in TBEP-induced neurobehavioral toxicity.

Tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) is an organophosphorus flame retardant that is an alternative to brominated flame retardants. Although TDCIPP can adversely affect human health, inform...

Bisphenol A (BPA) is a major constituent of plastic products, including epoxy resin containers, mobile phones, dental sealants, as well as electronic and medical equipment. BPA is recognized as an endocrine system-disrupting chemical which has toxic effects on the brain and reproductive system. However, little is known about the effects of co-exposure of BPA with allergens on the memory function and neurological as well as immunological biomarker levels. In this study, we examined the effects of intratracheal instillation of BPA on the memory function and neuroimmune biomarker levels using a mouse model of allergic asthma. Male C3H/HeJ Jcl mice were given three doses of BPA (0.0625 pmol, 1.25 pmol, and 25 pmol BPA/animal) intratracheally once a week, and ovalbumin (OVA) intratracheally every other week from 5 to 11 weeks old. At 11 weeks of age, a novel object recognition test was conducted after the final administration of OVA, and the hippocampi and hypothalami of the animals were collected after 24 h. The expression levels of the memory function-related genes N-methyl-D-aspartate (NMDA) receptor subunits, inflammatory cytokines, microglia markers, estrogen receptor-alpha, and oxytocin receptor were examined by real-time RT-PCR (real-time reverse transcription polymerase chain reaction) and immunohistochemical methods. Impairment of the novel object recognition ability was observed in the high-dose BPA-exposed mice with allergic asthma. In addition, the allergic asthmatic mice also showed downregulation of neurological biomarkers, such as NMDA receptor subunit NR2B in the hippocampus but no significant effect on immunological biomarkers in the hypothalamus. These findings suggest that exposure to high-dose BPA triggered impairment of memory function in the allergic asthmatic mice. This is the first study to show that, in the presence of allergens, exposure to high-dose BPA may affect memory by modulating the memory function-related genes in the hippocampus.

Bisphenol A (BPA) is used in the production of polycarbonate plastics and epoxy resins and found in many consumer products. Previous studies have reported that perinatal exposure to BPA through the oral route promotes the development of allergic airway inflammation. We investigated the effects of exposure to low-dose BPA during the juvenile period of development on allergic airway inflammation. Six-week-old male C3H/HeJ mice were intratracheally administered ovalbumin (OVA, 1 μg) every 2 weeks and/or BPA (0, 0.0625, 1.25, and 25 pmol/animal/week) once per week for 6 weeks. Following the final intratracheal instillation, we examined the cellular profile of the bronchoalveolar lavage fluid, histological changes and expression of inflammatory/anti-inflammatory mediators in the lungs, OVA-specific immunoglobulin (Ig) production, serum corticosterone levels, and changes in the lymphoid tissues (mediastinal lymph node (MLN) and spleen). Exposure to OVA + BPA enhanced inflammatory cell infiltration and protein expression of Th2 cytokines/chemokines (e.g. interleukin (IL)-13 and IL-33) in the lungs, OVA-specific immunoglobulin E (IgE) production, the numbers of total cells and activated antigen-presenting cells (MHC class II⁺ CD86⁺, CD11c⁺), as well as the production of Th2 cytokines (i.e. IL-4 and IL-5) and stromal cell-derived factor-1α in MLN cells compared to OVA exposure alone. These effects were more prominent with 0.0625 or 1.25 pmol/animal/week of BPA. Furthermore, exposure to OVA + BPA altered serum levels of anti-inflammatory corticosterone, estrogen receptor 2 messenger RNA (mRNA) expression in the lungs and spleen functionality. These findings suggest that low-dose BPA exposure may aggravate allergic airway inflammation by enhancing Th2 responses via disruption of the immune system.

Brominated flame retardants (BFRs) are widely used in consumer products. Their toxicological effects as endocrine disruptors have been partly examined. However, their immunological effects have not been elucidated. To evaluate the effects of BFRs on immune responses, we investigated whether BFRs affect phenotypes and the function of immune cells in vitro. Here we examined the commercial pentabromodiphenyl ether mixture (DE‐71), octabromodiphenyl ether mixture (DE‐79), decabromodiphenyl ether mixture (DE‐83R), hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA). Splenocytes and bone marrow (BM) cells were prepared from atopic prone NC/Nga mice. Splenocytes were exposed to each BFR for 24 h. BM cells were cultured with granulocyte macrophage‐colony stimulating factor (GM‐CSF) for 8 days and BM‐derived dendritic cells (BMDCs) were exposed to each BFR for 24 h. In another experiment, BM cells were cultured with GM‐CSF in the presence of each BFR for 6 days during BMDC differentiation. After exposure, cell surface molecule expression and cytokine production were investigated. Each BFR increased MHC class II and CD86 expression and interleukin (IL)‐4 production in splenocytes. DE‐71, HBCD and TBBPA increased T cell receptor (TCR) expression in splenocytes. In both experiments, all BFRs except TBBPA increased DEC205 expression in BMDCs. BMDCs that differentiated in the presence of HBCD showed enhanced MHC class II, CD80, CD86 and CD11c expression. The results demonstrate that some BFRs may stimulate immune cells. BFRs can induce or enhance immune/allergic responses by increasing antigen presentation‐related molecule expression and IL‐4 production. Copyright © 2012 John Wiley & Sons, Ltd.

Background: Diisononyl phthalate (DINP), a principal plasticizer in many polyvinyl chloride products, has been shown to have an adjuvant effect on immunoglobulin (Ig) production in mice. However, the effects of DINP on allergic diseases have not been fully elucidated. Objectives: In the present study we investigated the effects of DINP on atopic dermatitis (AD)-like skin lesions induced by Dermatophagoides pteronyssinus (Dp) in atopic-prone NC/Nga mice. Methods: Mice were injected intradermally with Dp on their ears and were exposed to DINP (0, 0.15, 1.5, 15, or 150 mg/kg/day) intraperitoneally. We evaluated clinical scores, ear thickening, histologic findings, protein expression of cytokines/chemokines in the ear, and serum levels of Ig and histamine. Furthermore, we investigated the effects of DINP on bone-marrow–derived dendritic cells (BMDCs) or splenocytes in vitro. After exposure to DINP (0–100 μM), cells were evaluated for phenotype and function. Results: DINP aggravated AD-like skin lesions related to Dp. The aggravation was consistent with eosinophilic inflammation, mast cell degranulation, and thymic stromal lymphopoietin (TSLP) expression in the ear. DINP enhanced the expression of cell surface activation markers on BMDCs and their production of TARC/CCL17 (thymus- and activation-regulated chemokine) and MDC/CCL22 (macrophage-derived chemokine), as well as their capacity to stimulate Dp-specific T-cell proliferation. DINP also enhanced interleukin-4 production and Dp-stimulated proliferation of splenocytes. Conclusions: DINP can aggravate AD-like skin lesions related to Dp. The mechanisms of the aggravation might be mediated, at least partly, through the TSLP-related activation of dendritic cells and by direct or indirect activation of the immune cells.