The impact of oral exposure to low‐dose tris(2‐butoxyethyl) phosphate in allergic asthmatic mice

• Published in: Journal of applied toxicology 2020-11, Vol.40 (11), p.1498-1510
• Main Authors: Yanagisawa, Rie, Koike, Eiko, Win‐Shwe, Tin‐Tin, Kawaguchi, Maiko, Takano, Hirohisa
• Format: Article
• Language: English
• Subjects: allergic asthma; Asthma; Bone marrow; Bromination; CC chemokine receptors; CCR2 protein; Cell activation; Cell number; Cell proliferation; Dendritic cells; Eotaxin; estrogen receptor; Estrogen receptors; Estrogens; Exposure; Flame retardants; Hypersensitivity; Interleukins; low‐dose effects; Lymph nodes; Microenvironments; Monocyte chemoattractant protein 1; mRNA; organophosphorus flame retardants; Ovalbumin; Retardants; Th2 response; tris(2‐butoxyethyl) phosphate
• ISSN: 0260-437X; 1099-1263
• DOI: 10.1002/jat.4001

Tris(2‐butoxyethyl) phosphate (TBEP) is a major organophosphorus flame retardant and has been widely increasing as a substitute for brominated flame retardants. TBEP may have adverse effects on human health; however, its impact on immune and allergic responses remains largely uncharacterized. In this study, the effects of low‐dose TBEP comparable with the level of actual human exposure to that of human tolerable daily intake on allergic asthmatic mice were explored. Five‐week‐old C3H/HeJSlc male mice consumed a diet containing approximately 0.02, 0.2 or 2 μg/kg/day TBEP and were intratracheally administrated ovalbumin (OVA) (1 μg/mouse every 2 weeks from 5 to 11 weeks of age). Exposure to 2 μg/kg/day TBEP with OVA tended to enhance allergic pulmonary inflammation and significantly elevated mRNA levels of interleukin‐5, eotaxin‐1 and estrogen receptor alpha (ERα) compared with OVA alone. In mediastinal lymph nodes (MLNs), TBEP (0.2 or 2 μg/kg/day) with OVA significantly increased in total cell number and promoted conventional dendritic cell activation than OVA alone; MLN cell proliferation by OVA restimulation was also enhanced in these groups. In the bone marrow (BM), TBEP (0.02 or 0.2 μg/kg/day) with OVA resulted in a net decrease in total cell number and fraction of CCR2+Gr‐1+ cells; the fraction of Gr‐1+ cells increased. In conclusion, oral exposure to low‐dose TBEP levels equivalent to tolerable daily intake may exacerbate allergic pulmonary inflammation by promoting a skewed T‐helper 2 cell response, upregulation of ERα and dysregulation of both MLN and BM microenvironments. We investigated the effects of oral exposure to low‐dose tris(2‐butoxyethyl) phosphate (TBEP) on allergic asthma mice. TBEP slightly enhanced allergic pulmonary inflammation via increase in the mRNA levels of interleukin‐5, eotaxin‐1 and estrogen receptor alpha. In mediastinal lymph nodes, TBEP + ovalbumin significantly increased total cell number and promoted conventional dendritic cell activation and allergen‐restimulated cell proliferation. Furthermore, there was slight dysregulation in the bone marrow microenvironments. Oral exposure to low‐dose TBEP levels equivalent to tolerable daily intake may exacerbate allergic responses.