Chih-Hsing Hung1-4, San-Nan Yang, 1-3, Po-Lin Kuo5, Yu-Te Chu3, Hui-Wen Chang3, Wan-Ju
Wei4, Shau-Ku Huang2,4,6*, Yuh-Jyh Jong,1-3*
Background: Exposure to environmental endocrine-disrupting chemicals (EDCs) is often
associated with dysregulated immune homeostasis, but the mechanisms of action remain unclear.
Objectives: The aim of this study was to test a hypothesis that EDCs regulate the functions of
human dendritic cells (DCs), a front-line, immunoregulatory cell type in contact with the
Methods: Circulating myeloid DCs (mDCs) from five subjects were investigated, and their
responses, with or without co-culture with autologous T cells, to two common EDCs, nonylphenol
(NP) and 4-octylphenol (4-OP), were measured. EDC-associated cytokine responses, signaling
events and histone modifications were examined by using ELISA, western blotting and chromatin
immunoprecipitation (ChIP) assay, respectively.
Results: In all cases, mDCs treated with NP or 4-OP demonstrated increased expression of TNF-α,
but decreased baseline and LPS-induced IL-10 production, which was partially reversible by an
estrogen receptor antagonist. Activation of the MKK3/6-p38 signaling pathway marked the effect
of NP on TNF-α expression, concomitant with enhanced levels of methyltranferase complex (MLL
and WDR5) in the nucleus, and of trimethylated H3K4, acetylated H3 as well as H4 at the TNFA
gene locus. Further, upregulated TNF-α expression was significantly suppressed in NP-treated
mDCs by a histone acetyltransferase inhibitor. In the presence of NP-treated mDCs, T cells showed
increased levels of IL-13, but decreased expression of IFN-γ.
Conclusions: These results suggest that NP and 4-OP may have functional effects on mDC's
response via, in part, the estrogen receptor, MKK3/6-p38 MAPK signaling pathway and histone
modifications, with subsequent influence on the T-cell cytokine responses.