We have investigated the influence of alkylphenol endocrine disrupters and the synthetic estrogen diethylstilbestrol (DES) on inositol-1,4,5-trisphosphate (IP3)-sensitive Ca2+ channels from porcine cerebellum and rat testicular membranes. All alkylphenols and DES inhibited the extent Of IP3-induced Ca2+ release (IICR) from both cerebellar and testicular microsomes. 4-n-nonylphenol was the most potent compound tested (IC50, 8 muM)- Inhibition of IICR was directly related to the length and hydrophobicity of the alkylphenol side chain. None of the alkylphenols or DES appeared to influence the concentration dependence of IICR nor did they have a significant effect on [H-3]IP3 binding to the membranes. An investigation of the effects of nonylphenol on the transient kinetics of IICR showed that it inhibited the rate constants for both the fast and the slow phases of IICR and also the extent of Ca2+ release. These results illustrate another mechanism by which these environmental pollutants can disrupt endocrine function without the involvement of estrogen receptors. (C) 2003 Elsevier Inc. All rights reserved.