Brien S E, Heaton J P, Racz W J, Adams M A
Department of Pharmacology & Toxicology, Queen's University, Kingston General Hospital, Ontario, Canada.
J Urol. 2000 Apr;163(4):1315-21.
Erectile function is testosterone dependent. For example, interference with either the levels or receptor binding of this steroid hormone may induce erectile dysfunction. Several environmental contaminants can interfere with the actions of endogenous hormones and have been termed 'endocrine disrupters.' p,p-DDE, a prominent and persistent metabolite of the insecticide DDT, has been shown to be an androgen receptor antagonist. The objective was to determine whether endocrine disrupters, as exemplified by p,p-DDE, are factors in the etiology of erectile dysfunction.
Using the established rat model of apomorphine-induced (80 microg./kg, s.c.) erections we assessed the dose-response effects of p,p-DDE in comparison to the known androgen receptor antagonist flutamide in acute (0.5 to 12 hours) and short-term (up to 8 weeks) experiments in both intact (Study 1) and castrated (Study 2) rats. As a follow up (Study 3), castrated rats treated with p,p-DDE were given increasing doses of testosterone (0.48 to 2.4 mg./kg., i.p.), eight weeks after p,p-DDE administration, to assess reversibility of p,p-DDE effect.
A single dose of flutamide (50 mg./kg., i.p.) was found to significantly decrease apomorphine-induced erections to less than 50% over 12 hours following flutamide administration with recovery of erectile response within 48 hours. In comparison, a single dose of p,p-DDE (500 mg./kg., i.p.) decreased apomorphine-induced erections for at least two weeks (1.15+/-0.3 versus 2.5+/-1.1). Castration significantly decreased apomorphine-induced erections to approximately 0.5 erections/30 minutes. Flutamide (50 mg./kg.; i.p.) or p,p-DDE (50 mg./kg.; i.p.) did not further suppress the apomorphine erections in castrated rats. Testosterone supplementation (480 microg./kg; s.c.) in vehicle treated castrated rats recovered erectile response to pre-castrated levels, whereas p,p-DDE treated castrated rats required 4 times the dose of testosterone (2 mg./kg.; s.c.) given to vehicle treated rats to recover erections.
The endocrine disrupter p,p-DDE can markedly interfere with erectile function and demonstrates persistence after a single dose. This supports our novel concept that environmental hormones may cause erectile dysfunction.
勃起功能依赖于睾酮。例如，干扰这种甾体激素的水平或受体结合可能会诱发勃起功能障碍。几种环境污染物能够干扰内源性激素的作用，被称为“内分泌干扰物”。p,p - DDE是杀虫剂滴滴涕的一种显著且持久的代谢产物，已被证明是一种雄激素受体拮抗剂。目的是确定以内分泌干扰物p,p - DDE为代表的这类物质是否为勃起功能障碍病因中的因素。
利用已建立的阿扑吗啡诱导（80微克/千克，皮下注射）勃起的大鼠模型，我们在完整大鼠（研究1）和去势大鼠（研究2）中进行了急性（0.5至12小时）和短期（长达8周）实验，评估了p,p - DDE与已知雄激素受体拮抗剂氟他胺相比的剂量反应效应。作为后续研究（研究3），在给予p,p - DDE八周后，对用p,p - DDE处理的去势大鼠给予递增剂量的睾酮（0.48至2.4毫克/千克，腹腔注射），以评估p,p - DDE效应的可逆性。
发现单次给予氟他胺（50毫克/千克，腹腔注射）可使阿扑吗啡诱导的勃起在给药后12小时内显著减少至不到50%，勃起反应在48小时内恢复。相比之下，单次给予p,p - DDE（500毫克/千克，腹腔注射）可使阿扑吗啡诱导的勃起减少至少两周（1.15±0.3对2.5±1.1）。去势显著降低了阿扑吗啡诱导的勃起，降至约0.5次勃起/30分钟。氟他胺（50毫克/千克；腹腔注射）或p,p - DDE（50毫克/千克；腹腔注射）并未进一步抑制去势大鼠的阿扑吗啡诱导的勃起。在接受载体处理的去势大鼠中补充睾酮（480微克/千克；皮下注射）可使勃起反应恢复到去势前水平，而用p,p - DDE处理的去势大鼠需要给予接受载体处理大鼠4倍剂量的睾酮（2毫克/千克；皮下注射）才能恢复勃起。
内分泌干扰物p,p - DDE可显著干扰勃起功能，且单次给药后具有持续性。这支持了我们的新观点，即环境激素可能导致勃起功能障碍。
