The endocrine disruptors nonylphenol and octylphenol exert direct effects on T cells to suppress Th1 development and enhance Th2 development

Some endocrine disrupting chemicals (EDCs) have been evidenced to affect cytokine production and lymphocyte proliferation. However, it is unknown whether EDCs disturb Th1/Th2 development. We chose alkylphenols that have been widely used as plastic additives and surfactants, and some of them are recognized as xenoestrogens. We examined whether they exert direct effects on T cells to suppress or enhance Th1/Th2 development. We used two experimental systems with isolated T cells in vitro. In one system, isolated CD4+CD8+ thymocytes differentiated into Th1 and Th2 by two transient stimulations and cytokine treatment. In the second system, purified naïve CD4+ T cells from DO11.10 T cell receptor-transgenic and RAG-2-deficient mice differentiate into Th1 and Th2 by the treatment with cytokines and antibodies to CD3 and CD28. In both systems, 1-10 microM of p-n-nonylphenol suppressed Th1 development and enhanced Th2 development, whereas estrogen by itself failed to affect Th1/Th2 development. p-n-Octylphenol elicited similar effects, but 4-nonylphenol and p-t-octylphenol elicited much weaker effects. p-n-Dodecylphenol or p-n-octylbenzene failed to affect Th1/Th2 development. Thus, the length and branching of the alkyl side chain appeared to affect the activity. Although some alkylphenols have been suggested to have a weak affinity to retinoic acid receptors (RAR) or progesterone receptor (PRGR), antagonists of RAR, PRGR, glucocorticoid receptor (GCR), or retinoid X receptors (RXR) failed to inhibit the activity. These results suggest that p-n-nonylphenol and p-n-octylphenol directly suppress Th1 development and enhance Th2 development through mechanisms independent of estrogen receptors, RAR, RXR, PRGR, and GCR.