Tapper Mark A, Denny Jeffrey S, Sheedy Barbara R, Kolanczyk Richard C, Saari Gavin, Hammermeister Dean E, Backe Will, Serrano Jose
Office of Research and Development, Center for Computational Toxicology and Exposure, Great Lakes Toxicology and Ecology Division, United States Environmental Protection Agency, Duluth, MN, United States.
United States Environmental Protection Agency (retired).
Environ Toxicol Chem. 2025 Apr 1;44(4):1091-1106. doi: 10.1093/etojnl/vgaf034.
Alkylcyclohexanones and alkylcyclohexanols are industrial chemicals produced in large volumes. Little is known regarding the estrogenic activity of these chemicals in aquatic species. A series of para-alkyl substituted hexanones and hexanols with varying chain length and branching were tested in a suite of in vitro rainbow trout binding assays and in an ex vivo rainbow trout liver slice/vitellogenin (Vtg) expression assay to assess estrogenic potential. Furthermore, the extent of biotransformation of these chemicals under test conditions was monitored. Cyclohexane, cyclohexanol, and 4-ethylcyclohexanol had no detectable estrogenic activity in these assays. Para substituted alkylcyclohexanones and alkylcyclohexanols with side chains containing three to six carbons were active in both assays. Alkylcyclohexanones and alkylcyclohexanols with other than para substitution were also estrogenic when tested in these assays. The binding affinity relative to estradiol in cytosol of active chemicals was low, ranging from 0.0016% to 0.000029%. Biotransformation of alkylcyclohexanones to alkylcyclohexanols occurred in the cytosol binding assay and in the liver slice assay, thus making those exposures a mixture of alcohol and ketone forms. Biotransformation did not occur in rainbow trout nuclear extract and recombinant binding assays; thus, the exposure in these assays was to only the dosed chemical. Both alkylcyclohexanones and alkylcyclohexanols bound to the estrogen receptor in these metabolically limited assays. Significant induction of Vtg mRNA expression was seen in slice exposed to chemicals with measurable binding affinities. Often the induction levels were below maximum efficacy and occurred at concentrations slightly lower than toxic concentrations. Therefore, while these chemicals produced an estrogenic effect, it is considerably weaker than that of the endogenous hormone and occurred at concentrations close to those which produce toxicity.
烷基环己酮和烷基环己醇是大量生产的工业化学品。关于这些化学品对水生物种的雌激素活性知之甚少。一系列具有不同链长和支化度的对烷基取代己酮和己醇在一套体外虹鳟鱼结合试验以及离体虹鳟鱼肝切片/卵黄蛋白原（Vtg）表达试验中进行了测试，以评估其雌激素潜力。此外，还监测了这些化学品在测试条件下的生物转化程度。环己烷、环己醇和4 - 乙基环己醇在这些试验中未检测到雌激素活性。侧链含有三至六个碳的对取代烷基环己酮和烷基环己醇在两种试验中均具有活性。在这些试验中测试时，非对取代的烷基环己酮和烷基环己醇也具有雌激素活性。活性化学品在胞质溶胶中相对于雌二醇的结合亲和力较低，范围为0.0016%至0.000029%。在胞质溶胶结合试验和肝切片试验中发生了烷基环己酮向烷基环己醇的生物转化，因此这些暴露是醇和酮形式的混合物。在虹鳟鱼核提取物和重组结合试验中未发生生物转化；因此，这些试验中的暴露仅针对给药的化学品。在这些代谢受限的试验中，烷基环己酮和烷基环己醇均与雌激素受体结合。在暴露于具有可测量结合亲和力的化学品的切片中观察到Vtg mRNA表达的显著诱导。诱导水平通常低于最大效力，且发生在略低于毒性浓度的浓度下。因此，虽然这些化学品产生了雌激素效应，但其比内源激素的效应弱得多，且发生在接近产生毒性的浓度下。
