Crossover Study on Human Exposure to Phthalates and Male Fertility

描述(由研究人员提供)：邻苯二甲酸酯是一类广泛使用的现代合成化学品，已在实验动物中显示为睾丸毒物。尽管美国普通民众广泛接触邻苯二甲酸盐，但关于其潜在健康风险的人体研究有限。在我们正在进行的关于环境和生殖健康的研究中，我们发现接触邻苯二甲酸二丁酯(DBP)与精液质量下降之间存在潜在的关联。出乎意料的是，我们发现一名男子尿中邻苯二甲酸单丁酯(MBP)的主要代谢物浓度比美国人口报告的第95个百分位数高出两个数量级。接触DBP的来源是用于治疗炎症性肠病(IBD)的Asacol(美沙拉明，含有DBP的肠衣)。根据尿中MBP浓度估算的DBP摄入量为224 5g/kg/d，高于美国环保局DBP的参考剂量(RfD)(100 5g/kg/d)。在其他男性中，我们已经证实Asacol会导致高DBP暴露。由于治疗IBD的一些药物中包含DBP，而用于相同适应症的其他药物中没有DBP，而且患者和处方者不太可能意识到他们与DBP的接触，因此有独特的机会实施创新设计，以研究高暴露于邻苯二甲酸盐对人类健康的影响。不太可能被潜在的医学适应症混淆，因为无效成分，即DBP，存在于用于给定适应症的一些药物中，而不存在于用于相同适应症的其他药物中。在这项拟议的研究中，我们将招募100名医生诊断为轻度IBD的育龄男性，他们服用美沙拉明。一些男性接受涂层中含有DBP邻苯二甲酸盐的美沙拉明治疗(例如Asacol)，而另一些男性接受涂层中不含DBP的美沙拉明治疗(例如Pentasa)。我们提出了一项交叉研究，其中男性参与了六次研究访问。前两次研究访问(相隔两周)包括在男子服用医生开出的美沙拉明药物(即Asacol或Pentasa)时收集基线精液、尿液和血液样本。第二次检查后，男性将被要求改用另一种美沙拉明产品。因此，在招募时服用阿萨科尔的男性被转换为宾萨，而在招募时服用潘塔萨的男性被转换为阿萨科尔。受试者继续服用替代的美沙拉明产品3个月，之后他们返回学习访问3和4(相隔两周)，并提供精液、尿液和血液样本。在学习访问4之后，这些人切换回他们原来的美沙拉明药物。经过3个月的“洗涤期”，每个受试者都会回到原来的药物治疗阶段，进行第5次和第6次学习访问(相隔两周)，提供精液、尿液和血样。该项目的具体目标是确定高暴露于DBP与男性生育能力的中间和临床标记之间的关联，包括精液质量、精子DNA损伤、生殖激素谱和精子转录谱。现代转录图谱技术(即微阵列和深度测序)为睾丸提供了一种非侵入性的替代技术。我们将评估它们作为暴露于DBP的生物标志物的用途，以反映影响男性生育的病理机制。总而言之，交叉策略是一个强大的设计，在这个设计中，我们将比较同一个男人服用Asacol(高DBP暴露)和服用Pentasa(低DBP暴露)时，男性生育能力生物标志物的变化。

DESCRIPTION (provided by investigator): Phthalates are a class of widely used modern synthetic chemicals that have been shown in experimental animals to be testicular toxicants. Although there is widespread exposure of the U.S. general population to phthalates, there are limited human studies on their potential health risks. In our ongoing study on the environment and reproductive health, we found a suggestive association between exposure to dibutyl phthalate (DBP) and reduced semen quality. Unexpectedly, we identified one man with urinary concentrations of monobutyl phthalate (MBP), the main DBP metabolite, that was two orders of magnitude higher than the 95th percentile reported in the U.S. population. The source of DBP exposure was Asacol (mesalamine, with enteric coating containing DBP) used to treat inflammatory bowel disease (IBD). The estimated DBP intake of 224 5g/kg/day, obtained from the urinary concentration of MBP, was higher than the U.S. EPA reference dose (RfD) for DBP (100 5g/kg/day). Among additional men, we have since confirmed that Asacol contributes to high DBP exposure. Because DBP is included in some medications to treat IBD but not in others used for the same indications, and patient's and prescriber's are unlikely to be aware of their exposure with respect to DBP, there is the unique opportunity to implement innovative designs to study the impact of high exposure to phthalates on human health. Confounding by underlying medical indication is unlikely because inactive ingredients, i.e., DBP, are present in some drugs used for a given indication but not in other drugs used for the same indication. In the proposed study, we will recruit 100 men of reproductive age with a physician diagnosis of mild IBD who were prescribed mesalamine. Some men are treated with mesalamine that contains DBP phthalate in the coating (e.g., Asacol) while some men are treated with mesalamine that does not contain DBP in the coating (e.g., Pentasa). We propose a crossover study in which men participate in six study visits. The first two study visits (two weeks apart) include collection of a baseline semen, urine and blood sample while the man is on his physician prescribed mesalamine medication (i.e., Asacol or Pentasa). After the second visit, men will be asked to switch to the other mesalamine product. Thus, men on Asacol at recruitment are switched to Pentasa, and those on Pentasa at recruitment are switched to Asacol. Subjects continue on the alternate mesalamine product for a 3-month 'washout' period after which they return for study visit 3 and 4 (two weeks apart) and provide a semen, urine and blood sample. After study visit 4, the men switch back to their original mesalamine medication. After a 3-month 'washout' period back on their original medication, each subject returns for study visit 5 and 6 (two weeks apart) to provide a semen, urine, and blood sample. The project specific aims are to determine the association of high exposure to DBP with intermediate and clinical markers of male fertility, including semen quality, sperm DNA damage, reproductive hormone profiles, and sperm transcript profiling. Modern techniques of transcript profiling (i.e., microarrays and deep sequencing) provide a non-invasive proxy for the testis. We will assess their use as biomarkers of exposure to DBP, reflective of the pathological mechanism impacting male fertility. In summary, the crossover strategy is a powerful design in which we will compare alterations in biomakers of male fertility in the same man when he is taking Asacol (high DBP exposure) as compared to when he is on Pentasa (low DBP exposure).