Estrogenic activity of dicofol with the human estrogen receptor: Isomer- and enantiomer-specific implications

Dicofol is a non-systemic acaricide/miticide currently registered in the US and Canada for use on a wide variety of crops. This agrochemical has been identified as a potential candidate substance for the United Nations Economic Commission for Europe (UN-ECE) Persistent Organic Pollutant (POP) Protocol and implicated as a potential “endocrine disrupting compound”. The technical product is usually synthesized from technical DDT and consists of approximately 80% and 20% of p,p′- and o,p′-dicofol isomers. The o,p′-substituted isomer of dicofol is chiral and may have enantiomer-specific activity; however, the stereospecific activity of o,p′-dicofol has not been reported. In this study, we examined the isomer- and enantiomer-specific endocrine disruption potential of dicofol using yeast-based steroid hormone receptor gene transcription assay designed with the human estrogen receptor (hER). Estrogenic activity of (+)-17-β estradiol (positive control), p,p′-dicofol, racemic o,p′-dicofol [(±)-o,p′-dicofol] and the individual o,p′-dicofol enantiomers was measured via quantification of β-galactosidase. The (±)-o,p′- and p,p′-dicofol were weak estrogen mimics (EC50: 4.2 × 10−6 and 1.6 × 10−6 M, respectively) relative to estradiol (3.7 × 10−10 M). For o,p′-dicofol, the β-galactosidase induction by (−)-o,p′-dicofol (EC50: 5.1 × 10−7 M) was greater than the racemic mixture. However, the (+)-o,p′-dicofol enantiomer was found to have negligible estrogenic activity. These data indicate that dicofol is a weak hER agonist due to activity of the achiral p,p′-isomer and (−)-o,p′-substituted enantiomer and emphasizes the influence of chemical structure and configuration on biological responses to exposure from chiral compounds.