The physiological and biochemical basis of potency thresholds modeled using human estrogen receptor alpha: implications for identifying endocrine disruptors
by:
Borgert CJ, Burgoon LD, Matthews JC
Borgert CJ, Burgoon LD, Matthews JC
Summary:
The endocrine system operates via ligand-receptor interactions, where ligand potency (affinity × efficacy) and concentration dictate physiological effects, governed by mass action laws relating affinity to receptor occupancy. Previously, we established a Human-Relevant Potency Threshold (HRPT) for ERα agonists at 1/10,000 the potency of 17β-estradiol (E2), as weak ligands (e.g., from botanicals) lack clinically observable estrogenic effects. Here, we hypothesize the HRPT stems from competition with the endogenous metabolic milieu (hormone precursors, metabolites). Fractional ERα occupancy calculations, incorporating normal circulating E2 and other endogenous ligands, show that exogenous ligands with potencies greater than 1/1,000 relative to 17β-estradiol may compete effectively against individual or mixed milieu components; those with relative potencies less than 1/1,000 cannot. Thus, the HRPT proposed originally (1/10,000 of E2) is conservative, arguing against estrogenic disruption potential. For potencies above 1/1,000 of E2, disruption is equivocal, requiring corroboration. Critically, the endogenous milieu drives the HRPT for both agonists and antagonists, providing a kinetics-based mechanistic rationale using established metabolic properties.
The endocrine system operates via ligand-receptor interactions, where ligand potency (affinity × efficacy) and concentration dictate physiological effects, governed by mass action laws relating affinity to receptor occupancy. Previously, we established a Human-Relevant Potency Threshold (HRPT) for ERα agonists at 1/10,000 the potency of 17β-estradiol (E2), as weak ligands (e.g., from botanicals) lack clinically observable estrogenic effects. Here, we hypothesize the HRPT stems from competition with the endogenous metabolic milieu (hormone precursors, metabolites). Fractional ERα occupancy calculations, incorporating normal circulating E2 and other endogenous ligands, show that exogenous ligands with potencies greater than 1/1,000 relative to 17β-estradiol may compete effectively against individual or mixed milieu components; those with relative potencies less than 1/1,000 cannot. Thus, the HRPT proposed originally (1/10,000 of E2) is conservative, arguing against estrogenic disruption potential. For potencies above 1/1,000 of E2, disruption is equivocal, requiring corroboration. Critically, the endogenous milieu drives the HRPT for both agonists and antagonists, providing a kinetics-based mechanistic rationale using established metabolic properties.