Crossover Study on Human Exposure to Phthalates and Male Fertility

人类接触邻苯二甲酸盐与男性生育能力的交叉研究

• 批准号: 8064776
• 负责人: RUSS B HAUSER
• 金额: $ 47.88万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064776
• 关键词: Affect; Age; Animal Model; Animals; Area; Back; Biological Markers; Birth; Blood; Blood specimen; Centers for Disease Control and Prevention (U.S.); Chemical Exposure; Chemicals; Child; Clinical; Clinical Markers; Collection; Cross-Over Studies; Crossover Design; DNA Damage; Development; Diagnosis; Dibutyl Phthalate; Dose; Drug usage; Endocrine; Enteral; Environment; Environmental Epidemiology; Environmental Health; Exposure to; Family; Fertility; Food Packaging; Food Processing; General Population; Health; Human; Inflammatory Bowel Diseases; Intake; Life; Medical; Mesalamine; Messenger RNA; National Health and Nutrition Examination Survey; Outcome; Patients; Pharmaceutical Preparations; Physicians; Plastics; Population; Pregnancy; Proxy; Public Health; Recruitment Activity; Reporting; Reproductive Health; Research Personnel; Risk; Self Care; Seminal fluid; Serum; Signal Transduction; Source; Synthesis Chemistry; Techniques; Testis; Testosterone; Toy; Transcript; Urine; Visit; cell motility; design; disorder prevention; experience; exposed human population; flexibility; inhibin B; innovation; male; man; men; molecular marker; monobutyl phthalate; novel; phthalates; pill; public health relevance; reproductive; reproductive hormone; sperm cell; sperm quality; toxicant; urinary

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). PUBLIC HEALTH RELEVANCE: Over the last several decades the U.S. male population has experienced a decline in semen quality. Phthalates are a family of widely used chemicals that adversely affect male fertility in animal models. The proposed crossover study will define the impact of high exposure to phthalates on clinical and molecular markers of male fertility requisite for a healthy child.

描述（由研究者提供）：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。虽然美国普通人群广泛接触邻苯二甲酸酯，但对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，我们发现暴露于邻苯二甲酸二丁酯（DBP）和精液质量下降之间存在暗示性关联。出乎意料的是，我们发现一名男性的尿中邻苯二甲酸单丁酯（MBP）浓度，DBP的主要代谢产物，比美国人群报告的第95百分位数高出两个数量级。DBP暴露的来源是用于治疗炎症性肠病（IBD）的Asacol（美沙拉嗪，肠溶包衣含DBP）。根据尿MBP浓度估算的DBP摄入量为224 5g/kg/d，高于美国EPA DBP参考剂量（100 5g/kg/d）。在其他男性中，我们已经证实Asacol有助于高DBP暴露。由于DBP包含在一些治疗IBD的药物中，但不包含在用于相同适应症的其他药物中，并且患者和处方者不太可能意识到他们对DBP的暴露，因此有独特的机会实施创新设计，以研究邻苯二甲酸酯高暴露对人类健康的影响。不太可能受到基础医学适应症的混淆，因为非活性成分，即，DBP存在于用于给定适应症的一些药物中，但不存在于用于相同适应症的其他药物中。在拟议的研究中，我们将招募100名医生诊断为轻度IBD的育龄男性，并开具美沙拉嗪。一些男性用涂层中含有DBP邻苯二甲酸酯的美沙拉嗪治疗（例如，Asacol），而一些男性用包衣中不含DBP的美沙拉嗪治疗（例如，Pentasa）。我们提出了一项交叉研究，其中男性参与六次研究访问。前两次研究访问（间隔两周）包括收集基线精液、尿液和血液样本，同时该男子正在接受医生开具的美沙拉嗪药物（即，Asacol或Pentasa）。第二次就诊后，男性将被要求改用其他美沙拉嗪产品。因此，在招聘时使用Asacol的男子转为使用Pentasa，而在招聘时使用Pentasa的男子转为使用Asacol。受试者继续使用替代的美沙拉嗪产品3个月的“洗脱”期，之后他们返回进行研究访视3和4（间隔两周），并提供精液、尿液和血液样本。在第4次研究访问后，这些人又回到了原来的美沙拉嗪药物治疗。在3个月的“洗脱”期后，恢复其原始药物治疗，每例受试者返回研究访视5和6（间隔两周），以提供精液、尿液和血液样本。该项目的具体目标是确定DBP高暴露与男性生育力的中间和临床标志物的相关性，包括精液质量、精子DNA损伤、生殖激素谱和精子转录谱。现代转录谱分析技术（即，微阵列和深度测序）提供了睾丸的非侵入性替代物。我们将评估它们作为DBP暴露生物标志物的用途，反映影响男性生育力的病理机制。总之，交叉策略是一种强大的设计，我们将比较同一名男性服用Asacol（高DBP暴露）与服用Pentasa（低DBP暴露）时男性生育力生物标志物的变化。 公共卫生相关性：在过去的几十年里，美国男性人口经历了精液质量下降。邻苯二甲酸酯是一种广泛使用的化学物质，在动物模型中对男性生育力产生不利影响。拟定的交叉研究将确定邻苯二甲酸酯高暴露对健康儿童所需的男性生育力的临床和分子标志物的影响。