Treinen K A, Dodson W C, Heindel J J
Developmental and Reproductive Toxicology Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Toxicol Appl Pharmacol. 1990 Nov;106(2):334-40. doi: 10.1016/0041-008x(90)90252-p.
Several phthalate esters are male and female reproductive toxicants in vivo. In the male, mono(2-ethylhexyl) phthalate (MEHP), the active metabolite of di(2-ethylhexyl) phthalate (DEHP), inhibits follicle stimulating hormone (FSH)-stimulated cAMP accumulation in the Sertoli cell in vitro. Since granulosa and Sertoli cells share several structural and functional characteristics, the effect of MEHP on granulosa cell intracellular cAMP accumulation was examined to elucidate a possible mechanism for DEHP reproductive toxicity in females. MEHP (100 microM) reduced FSH-stimulated cAMP accumulation in granulosa cells by 40% after a 24-hr preincubation. Significant inhibition of cAMP accumulation by MEHP occurred by 15 hr and MEHP did not affect the dose of FSH which resulted in half-maximal stimulation. Detailed investigations regarding the mechanism of MEHP inhibition were conducted using cholera toxin, forskolin, and isoproterenol. In contrast to FSH, MEHP did not affect the ability of these compounds to stimulate cAMP accumulation. In addition, a functional endpoint of granulosa cell function, progesterone production, was inhibited in a dose-dependent manner by MEHP. Further experiments will be necessary to determine the significance of these findings to in vivo toxicity, but these experiments describe a specific site of action of MEHP in vitro which may be related to the in vivo female reproductive toxicity of phthalate esters.
几种邻苯二甲酸酯在体内是雄性和雌性生殖毒物。在雄性中，邻苯二甲酸二（2-乙基己基）酯（DEHP）的活性代谢物单（2-乙基己基）邻苯二甲酸酯（MEHP）在体外抑制支持细胞中促卵泡激素（FSH）刺激的cAMP积累。由于颗粒细胞和支持细胞具有一些结构和功能特征，因此研究了MEHP对颗粒细胞内cAMP积累的影响，以阐明DEHP对雌性生殖毒性的可能机制。预孵育24小时后，MEHP（100 microM）使颗粒细胞中FSH刺激的cAMP积累减少了40%。MEHP在15小时时对cAMP积累产生显著抑制，且MEHP不影响导致最大刺激量一半的FSH剂量。使用霍乱毒素、福斯可林和异丙肾上腺素对MEHP抑制机制进行了详细研究。与FSH不同，MEHP不影响这些化合物刺激cAMP积累的能力。此外，颗粒细胞功能的一个功能终点——孕酮产生，被MEHP以剂量依赖的方式抑制。需要进一步的实验来确定这些发现对体内毒性的意义，但这些实验描述了MEHP在体外的一个特定作用位点，这可能与邻苯二甲酸酯的体内雌性生殖毒性有关。
