Effects of plasticizers and their mixtures on estrogen receptor and thyroid hormone functions

Plasticizers are additives used to increase the flexibility or plasticity of the material to which they are added, normally rigid plastic and as additives in paint and adhesives. They are suspected to interfere with the endocrine system, including the estrogen and the thyroid hormone (TH) systems. We investigated in vitro the thyroid hormone-like and estrogenic activities of a range of widely used plasticizers and phenols including benzyl butyl phthalate (BBP), dibutyl phthalate (DBP), dioctyl phthalate (DOP), diisodecyl phthalate (DIDP), diisononyl phthalate (DINP), di(2-ethylhexyl) phthalate (DEHP), bis(2-ethylhexyl) adipate (DEHA), 4-tert-octylphenol (tOP), 4-chloro-3-methylphenol (CMP), 2,4-dichlorophenol (2,4-DCP), 2-phenylphenol (2-PP) and resorcinol. The TH disrupting potential was determined by the effect on the TH-dependent rat pituitary GH3 cell proliferation (T-screen). The estrogenic activities of the compounds were assessed in MVLN cells, stably transfected with an estrogen receptor (ER) luciferase reporter vector. Furthermore, the combined effect of a multi-components mixture of six plasticizers was evaluated for its estrogenic and TH-like activities. All the tested compounds, but 2-PP, significantly affected the GH3 cell proliferation. tOP, BBP and DBP activated ER transactivity, whereas DEHP antagonized the 17beta-estradiol induced ER function. The mixture significantly induced ER transactivity in an additive manner, whereas in the T-screen, the observed mixture effect was lower than predicted, suggesting a potential antagonizing effect of the mixture. In conclusion, the tested plasticizers and phenols elicited endocrine-disrupting potential that can be mediated via interference with the estrogen and TH systems. Moreover, the observed mixture effect stresses the importance of considering the combined effect of the compounds for risk assessment of human health.