Interaction of organophosphate pesticides and related compounds with the androgen receptor.

Abstract

Identification of several environmental chemicals capable of binding to the androgen receptor (AR) and interfering with its normal function has heightened concern about adverse effects across a broad spectrum of environmental chemicals. We previously demonstrated AR antagonist activity of the organophosphate (OP) pesticide fenitrothion. In this study, we characterized AR activity of analogues of fenitrothion to probe the structural requirements for AR activity among related chemicals. AR activity was measured using HepG2 human hepatoma cells transfected with human AR plus an androgen-responsive luciferase reporter gene, MMTV-luc. AR antagonist activity decreased as alkyl chain length of the phosphoester increased, whereas electron-donating properties of phenyl substituents of the tested compounds did not influence AR activity. Oxon derivatives of fenitrothion, which are more likely to undergo hydrolytic degradation, had no detectable AR antagonist activity. Molecular modeling results suggest that hydrogen-bond energies and the maximum achievable interatomic distance between two terminal H-bond capable sites may influence both the potential to interact with the AR and the nature of the interaction (agonist vs. antagonist) within this series of chemicals. This hypothesis is supported by the results of recent AR homology modeling and crystallographic studies relative to agonist- and antagonist-bound AR complexes. The present results are placed in the context of structure-activity knowledge derived from previous modeling studies as well as studies aimed toward designing nonsteroidal antiandrogen pharmaceuticals. Present results extend understanding of the structural requirements for AR activity to a new class of nonsteroidal, environmental, OP-related chemicals.

QSAR Model for Androgen Receptor Antagonism - Data from CHO Cell Reporter Gene Assays

“…chemicals with AR antagonism in CHO cells were inactive in MDA cells with steroids dominating, making up three (progesterone, cyproterone acetate and 17β-estradiol) out of four chemicals [4,28,53]. The fourth chemical was chlordane [2,34,54]. This disagreement for chlordane was also reported previously by Aït-Aïssa et al [34].…”

Anti-androgenic activities of environmental pesticides in the MDA-kb2 reporter cell line

“…c: 1: (Kelce et al, 1994); 2: (Sohoni and Sumpter 1998); 3: (Andersen et al, 2002); 4: (Kelce et al, 1995); 5: (Kojima et al, 2004); 6: (Tamura et al, 2003); 7: (Lemaire et al, 2004), 8: (Sultan et al, 2001); 9: (Yamada et al, 2005); 10: (Xu et al, 2008); 11: (Scippo et al, 2004).…”

In vivo alternative assessment of the chemicals that interfere with anterior pituitary POMC expression and interrenal steroidogenesis in POMC: EGFP transgenic zebrafish

“…However, some OPs have been positively associated with certain developmental and reproductive effects. Moreover, some have been suggested as potent androgen receptor antagonists (Tamura et al, 2003). This emphasizes the need for further studies on the endocrine potential of the chemicals.…”