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-beta 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 beta-galactosidase. The (+/-)-o,p'- and p,p'-dicofol were weak estrogen mimics (EC(50): 4.2 x 10(-6) and 1.6 x 10(-6)M, respectively) relative to estradiol (3.7 x 10(-10)M). For o,p'-dicofol, the beta-galactosidase induction by (-)-o,p'-dicofol (EC(50): 5.1 x 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.
Hoekstra
Paul F
PF
National Water Research Institute, Environment Canada, Burlington, ON, Canada. paul.hoekstra@syngenta.com
Burnison
B Kent
BK
Garrison
A Wayne
AW
Neheli
Tannis
T
Muir
Derek C G
DC
D004010:Dicofol / Q000737:chemistry / Q000633:toxicity*; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D006801:Humans; D007306:Insecticides / Q000737:chemistry / Q000633:toxicity*; D007536:Isomerism; D011960:Receptors, Estrogen / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D001616:beta-Galactosidase / Q000378:metabolism
D004968:Estrogens, Non-Steroidal; D007306:Insecticides; D011960:Receptors, Estrogen; D001616:beta-Galactosidase; D004010:Dicofol