Orner G A, Hendricks J D, Arbogast D, Williams D E
Toxicology Program, Oregon State University, Corvallis 97331-6602, USA.
Toxicol Appl Pharmacol. 1996 Dec;141(2):548-54. doi: 10.1006/taap.1996.0321.
Dehydroepiandrosterone (DHEA) and its sulfate conjugate are the major circulating steroids in human plasma. Low levels of these adrenal steroids are associated with a number of human diseases including certain cancers. In animal studies, DHEA is chemopreventive toward both spontaneous and chemically induced cancers. A potential concern for long-term usage of DHEA in humans is the finding that DHEA is hepatocarcinogenic in rats. The human health risk has been thought to be minimal, however, as the mechanism of DHEA hepatocarcinogenesis is assumed to be due to its properties as a peroxisome proliferator, a class of compounds to which humans are relatively insensitive. Recently, we have found DHEA to be a potent promoter of aflatoxin B1-initiation as well as a complete hepatocarcinogen in the rainbow trout, a species which is also insensitive to peroxisome proliferators. In order to determine the initiator- and tissue-specificity of DHEA promotion, we examined the effects of DHEA on N-methyl-N'-nitro-nitrosoguanidine (MNNG)-initiated carcinogenesis. Trout fry were initiated by a bath exposure (30 min at 35 ppm) to MNNG and then fed DHEA at levels of 0, 55, 111, 222, 444, or 888 ppm for 7 months. DHEA increased liver tumor incidence, multiplicity, and size in a dose-dependent manner. The liver tumor incidence ranged from 0 in the MNNG-initiated controls to 99% in initiated trout fed 888 ppm DHEA. The latter represents a potential synergistic interaction in liver between MNNG and DHEA, as tumor incidence in sham-initiated trout fed this level of DHEA was 41%. The kidney tumor incidence was also enhanced two- and threefold over initiated controls by 111 and 888 ppm DHEA, respectively. In contrast, the total number of stomach and swim bladder tumors was reduced by DHEA treatment. This study demonstrates differential effects of DHEA on MNNG-initiated carcinogenesis in liver, kidney, stomach, and swim bladder.
脱氢表雄酮（DHEA）及其硫酸酯共轭物是人体血浆中主要的循环甾体激素。这些肾上腺甾体激素水平较低与包括某些癌症在内的多种人类疾病相关。在动物研究中，DHEA对自发性和化学诱导性癌症均具有化学预防作用。长期在人体中使用DHEA的一个潜在问题是发现DHEA在大鼠中具有致癌性。然而，人们认为对人类健康的风险极小，因为DHEA致癌的机制被认为是由于其作为过氧化物酶体增殖剂的特性，而人类对这类化合物相对不敏感。最近，我们发现DHEA是黄曲霉毒素B1启动的强效促进剂，也是虹鳟鱼中的完全致癌物，虹鳟鱼对过氧化物酶体增殖剂也不敏感。为了确定DHEA促进作用的启动子和组织特异性，我们研究了DHEA对N-甲基-N'-硝基-N-亚硝基胍（MNNG）启动的致癌作用的影响。将虹鳟鱼苗通过浸浴暴露（在35 ppm下30分钟）于MNNG进行启动，然后以0、55、111、222、444或888 ppm的水平喂食DHEA 7个月。DHEA以剂量依赖性方式增加肝脏肿瘤的发生率、多发性和大小。肝脏肿瘤发生率在MNNG启动的对照组中为0，在喂食888 ppm DHEA的启动虹鳟鱼中为99%。后者代表了MNNG和DHEA在肝脏中的潜在协同相互作用，因为喂食该水平DHEA的假启动虹鳟鱼的肿瘤发生率为41%。DHEA处理也分别使肾脏肿瘤发生率比启动对照组提高了两倍和三倍。相比之下，DHEA处理使胃和鳔肿瘤的总数减少。这项研究证明了DHEA对MNNG启动的肝脏、肾脏、胃和鳔致癌作用的不同影响。
