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).
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.
|Nassan, Feiby L; Coull, Brent A; Skakkebaek, Niels E et al. (2018) A crossover-crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men. Environ Res 160:121-131|
|Nassan, Feiby L; Coull, Brent A; Skakkebaek, Niels E et al. (2016) A crossover-crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and semen quality in men with inflammatory bowel disease. Environ Int 95:120-30|
|Wu, Haotian; Hauser, Russ; Krawetz, Stephen A et al. (2015) Environmental Susceptibility of the Sperm Epigenome During Windows of Male Germ Cell Development. Curr Environ Health Rep 2:356-66|
|Jodar, Meritxell; Sendler, Edward; Moskovtsev, Sergey I et al. (2015) Absence of sperm RNA elements correlates with idiopathic male infertility. Sci Transl Med 7:295re6|
|Hait, Elizabeth J; Calafat, Antonia M; Hauser, Russ (2014) Urinary phthalate metabolite concentrations among men with inflammatory bowel disease on mesalamine therapy. Endocr Disruptors (Austin) 1:|
|Mao, Shihong; Sendler, Edward; Goodrich, Robert J et al. (2014) A comparison of sperm RNA-seq methods. Syst Biol Reprod Med 60:308-15|
|Cantonwine, David E; Hauser, Russ; Meeker, John D (2013) Bisphenol A and Human Reproductive Health. Expert Rev Obstet Gynecol 8:|
|Mao, Shihong; Goodrich, Robert J; Hauser, Russ et al. (2013) Evaluation of the effectiveness of semen storage and sperm purification methods for spermatozoa transcript profiling. Syst Biol Reprod Med 59:287-95|
|Sendler, Edward; Johnson, Graham D; Mao, Shihong et al. (2013) Stability, delivery and functions of human sperm RNAs at fertilization. Nucleic Acids Res 41:4104-17|
|Johnson, G D; Sendler, E; Lalancette, C et al. (2011) Cleavage of rRNA ensures translational cessation in sperm at fertilization. Mol Hum Reprod 17:721-6|