Feiby L. Nassan

A crossover–crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and semen quality in men with inflammatory bowel disease

BACKGROUND Phthalates are widely used chemicals with ubiquitous exposure. Dibutyl-phthalate (DBP), a male reproductive toxicant in animals, is understudied in humans. Some mesalamine medications used to treat inflammatory bowel disease (IBD) have DBP in their coating, whereas other mesalamine formulations do not. OBJECTIVES Taking advantage of differences in mesalamine formulations, we investigated whether high-DBP exposure from mesalamine medications was associated with decreased semen parameters. METHODS 73 men with IBD taking mesalamine participated in a crossover-crossback prospective study. Men taking non-DBP containing mesalamine at baseline i.e., background exposure, crossed-over for four months to high-DBP mesalamine and then crossed-back for four months to their non-DBP mesalamine (B1HB2-arm;Background1-High-Background2) and vice versa for men taking high-DBP mesalamine at baseline (H1BH2-arm;High1-Background-High2). Men provided up to six semen samples (2: baseline, 2: crossover and 2: crossback). RESULTS We estimated crossover, crossback and carryover effects using linear mixed models adjusted for abstinence time, age, season and duration on high-DBP mesalamine at baseline. Semen parameters in B1HB2-arm (26 men, 133 samples) decreased after high-DBP mesalamine exposure (crossover versus baseline), especially motility parameters, and continued to decrease further even after crossback to non-DBP mesalamine (crossback versus crossover). The cumulative carryover effect of high-DBP (crossback versus baseline) was a decrease of % total sperm motility by 7.61(CI:-13.1, -2.15), % progressive sperm motility by 4.23(CI:-8.05, -0.4) and motile sperm count by 26.0% (CI:-46.2%, 1.7%). However, H1BH2-arm (47 men, 199 samples) had no significant change during crossover or crossback. CONCLUSIONS Men newly exposed to high-DBP mesalamine for four months had a cumulative reduction in several semen parameters, primarily sperm motility, that was more pronounced and statistically significant even after exposure ended for four months.

Personal Care Product Use in Men and Urinary Concentrations of Select Phthalate Metabolites and Parabens: Results from the Environment And Reproductive Health (EARTH) Study

Background: Personal care products (PCPs) are exposure sources to phthalates and parabens; however, their contribution to men’s exposure is understudied. Objectives: We examined the association between PCP use and urinary concentrations of phthalate metabolites and parabens in men. Methods: In a prospective cohort, at multiple study visits, men self-reported their use of 14 PCPs and provided a urine sample (2004–2015, Boston, MA). We measured urinary concentrations of 9 phthalate metabolites and methylparaben, propylparaben, and butylparaben. We estimated the covariate-adjusted percent change in urinary concentrations associated with PCP use using linear mixed and Tobit mixed regressions. We also estimated weights for each PCP in a weighted binary score regression and modeled the resulting composite weighted PCP use. Results: Four hundred men contributed 1,037 urine samples (mean of 3/man). The largest percent increase in monoethyl phthalate (MEP) was associated with use of cologne/perfume (83%, p-value<0.01) and deodorant (74%, p-value<0.01). In contrast, the largest percent increase for parabens was associated with the use of suntan/sunblock lotion (66–156%) and hand/body lotion (79–147%). Increases in MEP and parabens were generally greater with PCP use within 6 h of urine collection. A subset of 10 PCPs that were used within 6 h of urine collection contributed to at least 70% of the weighted score and predicted a 254–1,333% increase in MEP and parabens concentrations. Associations between PCP use and concentrations of the other phthalate metabolites were not statistically significant. Conclusions: We identified 10 PCPs of relevance and demonstrated that their use within 6 h of urine collection strongly predicted MEP and paraben urinary concentrations. https://doi.org/10.1289/EHP1374

Birth Outcomes in a Prospective Pregnancy–Birth Cohort Study of Environmental Risk Factors in Kuwait: The TRACER Study

BACKGROUND Rapid development and westernisation in Kuwait and other Gulf states have been accompanied by rising rates of obesity, diabetes, asthma, and other chronic conditions. Prenatal experiences and exposures may be important targets for intervention. We undertook a prospective pregnancy-birth cohort study in Kuwait, the TRansgenerational Assessment of Childrens Environmental Risk (TRACER) Study, to examine prenatal risk factors for early childhood obesity. This article describes the methodology and results of follow-up through birth. METHODS Women were recruited at antenatal clinical visits. Interviewers administered questionnaires during the pregnancy and collected and banked biological samples. Children are being followed up with quarterly maternal interviews, annual anthropometric measurements, and periodic collection of biosamples. Frequencies of birth outcomes (i.e. stillbirth, preterm birth, small and large for gestational age, and macrosomia) were calculated as a function of maternal characteristics and behaviours. RESULTS Two thousand four hundred seventy-eight women were enrolled, and 2254 women were followed to delivery. Overall, frequencies of stillbirth (0.6%), preterm birth (9.3%), and small for gestational age (7.4%) were comparable to other developed countries, but not strongly associated with maternal characteristics or behaviours. Macrosomia (6.1%) and large for gestational age (23.0%) were higher than expected and positively associated with pre-pregnancy maternal overweight/obesity. CONCLUSIONS A large birth cohort has been established in Kuwait. The collected risk factors and banked biosamples will allow examination of the effects of prenatal exposures on the development of chronic disease in children. Initial results suggest that maternal overweight/obesity before pregnancy should be targeted to prevent macrosomia and its associated sequelae of childhood overweight/obesity.

What Does a Single Semen Sample Tell You? Implications for Male Factor Infertility Research

Semen parameters are variable within individuals, but it is unclear whether 1 semen sample could represent a mans long-term average values in epidemiologic studies. Between 2005 and 2014, a total of 329 men from a fertility clinic in Boston, Massachusetts, provided 768 semen samples as part of the Environment and Reproductive Health (EARTH) Study. Total sperm count, sperm concentration, morphology, motility, and ejaculate volume were assessed. We used linear mixed models to compare values from mens first semen samples with their long-term averages and to calculate intraclass correlation coefficients for each parameter. We calculated positive predictive values (PPVs) and negative predictive values (NPVs) by comparing agreement in classification according to World Health Organization reference limits. There were no differences in mean semen parameters between mens first samples and the remaining replicates. Intraclass correlation coefficients ranged from 0.61 for morphology to 0.75 for concentration, indicating consistently greater between-man variability than within-man variability. Nevertheless, using 1 sample alone resulted in high NPVs but low PPVs (range, 43%-91%). The average of 2 samples was needed to achieve high PPVs (range, 86%-100%) and NPVs (range, 91%-100%). We conclude that 1 semen sample may suffice for studies aimed at identifying average differences in semen quality between individuals. Studies aimed at classifying men based on World Health Organization reference limits may benefit from collection of 2 or more samples.

The Environment and Reproductive Health (EARTH) Study: A Prospective Preconception Cohort

Abstract STUDY QUESTION Do environmental exposures, diet and lifestyle factors impact reproductive and pregnancy outcomes among subfertile couples attending a fertility clinic? SUMMARY ANSWER Environmental chemicals exposure in men and women were associated with reduced fertility and a higher risk of adverse outcomes, whereas some dietary factors improved the probability of successful reproductive outcomes. WHAT IS KNOWN ALREADY Accumulating epidemiologic evidence has shown associations of environmental chemicals and nutritional factors with reproductive and pregnancy outcomes. However, few studies have been designed to assess these factors simultaneously, and even fewer have collected such data among both men and women in the preconception period. Furthermore, early and sensitive reproductive endpoints (e.g. fertilization, implantation, biochemical pregnancy loss) are largely unobservable in population-based designs. STUDY DESIGN SIZE, DURATION The Environment and Reproductive Health (EARTH) Study is an ongoing prospective preconception cohort designed to investigate the impact of environmental, nutritional and lifestyle factors in both women and men on fertility and pregnancy outcomes. The study has been ongoing since 2004 and has recruited 799 women and 487 men (447 couples; 40 men joined without female partners) as of June 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS The study recruits women aged 18–45 years and men aged 18–55 years seeking fertility evaluation and treatment at a large academic hospital fertility center. Women and men are eligible to join either independently or as a couple. Participants are followed from study entry throughout each fertility treatment cycle, once per trimester of pregnancy (for those achieving pregnancy), and up to labor and delivery, or until they discontinue treatment or withdraw from the study. The study prospectively collects a combination of biological samples (e.g. blood, urine, semen), self-reported questionnaire data (including a validated food frequency questionnaire) and medical information abstracted from fertility clinic and hospital records. MAIN RESULTS AND THE ROLE OF CHANCE Among women in this cohort, higher urinary concentrations of some phthalate metabolites were associated with reduced oocyte yields, lower likelihood of clinical pregnancy, increased risk of pregnancy loss and lower likelihood of live birth following infertility treatment. Certain urinary phthalate metabolite concentrations among men was also associated with decreased odds of implantation and live birth. Maternal soy and folate intake significantly modified the association between bisphenol A (BPA) and IVF outcomes in women. While the EARTH Study has tested many a priori hypotheses, multiple comparisons were undertaken, and we cannot rule out the possibility that some of findings may be spurious or due to chance. LIMITATIONS REASONS FOR CAUTION While the fertility clinic setting provides the opportunity to measure environmental exposures, diet and lifestyle factors across different windows of vulnerability and to evaluate their potential effect on critical early fertility, pregnancy and delivery outcomes, the findings may be less generalizable to naturally conceived pregnancies. WIDER IMPLICATIONS OF THE FINDINGS The EARTH Study is one of the few cohorts designed to examine multiple windows of vulnerability, including the paternal and maternal preconception windows and the periconception and prenatal windows, in pregnancy. It is also one of the few human studies that has assessed potential interactions between environmental exposures and dietary factors. STUDY FUNDING/COMPETING INTEREST(S) The EARTH Study has been funded by the National Institute of Environmental Health Sciences since its inception in 2004. The authors declare no competing interests. TRIAL REGISTRATION NUMBER n/a.

A crossover-crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men.

Background Phthalates, such as dibutyl phthalate (DBP), are endocrine disruptors used in some medication coatings e.g., mesalamine to treat inflammatory bowel disease (IBD). Objectives Taking advantage of different mesalamine formulations with/without DBP, we assessed whether DBP from mesalamine (>1000x background) altered serum hormones. Methods Men (N=73) with IBD participated in a crossover‐crossback prospective study and provided up to 6 serum samples (2:baseline, 2:crossover, 2:crossback). Men on non‐DBP mesalamine (background) at baseline crossed‐over for 4 months to DBP‐mesalamine (high) and then crossed‐back for 4 months to non‐DBP mesalamine (B1HB2‐arm) and vice versa for men on DBP‐mesalamine at baseline (H1BH2‐arm). We divided H1BH2‐arm at the median (H1<3yrs or H1≥3yrs). We estimated crossover and crossback % changes in serum reproductive hormones using multivariable linear mixed effect models. Results When B1HB2‐arm (26 men,134 samples) crossed‐over, luteinizing hormone decreased 13.9% (95% confidence interval(CI): −23.6,−3.0) and testosterone, inhibin‐B, and follicle‐stimulating hormone (FSH) marginally decreased; after crossback all increased 8–14%. H1BH2‐arm, H1≥3yrs (25 men,107samples) had no changes at crossover or crossback whereas in H1BH2‐arm,H1<3yrs (22 men,100 samples) after crossover, inhibin‐B increased 13.2% (CI: 4.2,22.9), FSH decreased 9.9% (CI: −17.9,−1.1) and after crossback, inhibin‐B further increased 11.3%, and FSH marginally increased. Conclusions High‐DBP exposure may disrupt pituitary‐gonadal hormones that largely reversed after exposure removal, but only in men with no or short previous high‐exposure history. Paradoxically, men with longer duration of high‐DBP exposure, exposure removal did not change hormone levels, suggesting that long‐term high‐DBP exposure may alter the pituitary‐gonadal axis and make it insensitive to exposure changes. HighlightsMesalamine medications with coatings that contain dibutyl phthalate (DBP) lead to very high DBP exposure.New exposure to high DBP from mesalamine medications disrupted pituitary‐gonadal hormones in adult men.Among men with no or short previous high DBP exposure, the hormone disruption was reversed after exposure removal.Long term high DBP exposure may alter the pituitary‐gonadal axis and make it insensitive to removal of exposure.

Characterizing the effect of endocrine disruptors on human health: The role of epidemiological cohorts

Research on endocrine disruptors (EDs) developed from numerous disciplines. In this concert of disciplines, epidemiology is central to inform on the relevance for humans of mechanisms and dose-response functions identified in animals, to characterize the health impact (number of attributable disease cases), the cost associated with ED exposure, and the efficiency of the measures taken to limit exposure. Here, we present epidemiological tools to draw valid inference regarding effects of potential EDs. Epidemiology is generally observational, requiring care to control confounding bias. Many potential EDs have a short biological half-life; approaches relying on repeated biospecimens sampling allow limiting exposure misclassification and the resulting bias. For non-persistent compounds, couple-child cohorts are a central study design. Cohorts can now rely on molecular biology approaches to characterize exposures and intermediate pathways, which corresponds to the advent of molecular epidemiology and allows stronger interactions between epidemiology, toxicology, and molecular epidemiology to characterize the health effects of EDs.

Residential distance to major roadways and semen quality, sperm DNA integrity, chromosomal disomy, and serum reproductive hormones among men attending a fertility clinic

OBJECTIVE We examined associations of residential distance to major roadways, as a proxy for traffic-related air pollution exposures, with sperm characteristics and male reproductive hormones. DESIGN The cohort included 797 men recruited from Massachusetts General Hospital Fertility Center between 2000 and 2015 to participate in fertility research studies. MATERIALS AND METHODS Men reported their residential addresses at enrollment and provided 1-6 semen samples and a blood sample during follow-up. We estimated the Euclidean distance to major roadways (e.g. interstates and highways: limited access highways, multi-lane highways (not limited access), other numbered routes, and major roads) using information from the Massachusetts Department of Geographic Information Systems. Semen parameters (1238 semen samples), sperm DNA integrity (389 semen samples), chromosomal disomy (101 semen samples), and serum reproductive hormones (405 serum samples) were assessed following standard procedures. RESULTS Men in this cohort were primarily Caucasian (86%), not current smokers (92%), with a college or higher education (88%), and had an average age of 36 years and BMI of 27.7 kg/m2. The median (interquartile range) residential distance to a major roadway was 111 (37, 248) meters. Residential proximity to major roadways was not associated with semen parameters, sperm DNA integrity, chromosomal disomy, or serum reproductive hormone concentrations. The adjusted percent change (95% CI) in semen quality parameters associated with a 500 m increase in residential distance to a major roadway was -1.0% (-6.3, 4.5) for semen volume, 4.3% (-5.8, 15.7) for sperm concentration, 3.1% (-7.2, 14.5) for sperm count, 1.1% (-1.2, 3.4) for % total motile sperm, and 0.1% (-0.3, 0.5) for % morphologically normal sperm. Results were consistent when we modeled the semen parameters dichotomized according to WHO 2010 reference values. CONCLUSION Residential distance to major roadways, as a proxy for traffic-related air pollution exposure, was not related to sperm characteristics or serum reproductive hormones among men attending a fertility clinic in Massachusetts.

Dibutyl-phthalate exposure from mesalamine medications and serum thyroid hormones in men

BACKGROUND Dibutyl phthalate (DBP) is an endocrine disruptor and used in some medication coatings, such as mesalamine for treatment inflammatory bowel disease (IBD). OBJECTIVES To determine whether high-DBP from some mesalamine medications alters thyroid function. METHODS Seventy men with IBD, without thyroid disease or any radiation history participated in a crossover-crossback prospective study and provided up to 6 serum samples (2:baseline, 2:crossover, 2:crossback). Men on non-DBP mesalamine (background exposure) at baseline crossed-over to DBP-mesalamine (high exposure) then crossed-back to non-DBP mesalamine (B1HB2-arm) and vice versa for men on DBP-mesalamine at baseline (H1BH2-arm). Serum concentrations of total triiodothyronine (T3), total thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb). RESULTS After crossover in B1HB2-arm (26 men, 134 samples), T3 decreased 10% (95% confidence interval (CI): 14%,-5%), T3/T4 ratio decreased 8% (CI: 12%,-3%), TPOAb, and TgAb concentrations decreased, 11% (-20%, -2%) and 15% (-23%, -5%), respectively; after crossback, they increased. When men in the H1BH2-arm (44 men, 193 samples) crossed-over, T3 decreased 7% (CI: -11%, -2%) and T3/T4 ratio decreased 6% (CI: -9%, -2%). After crossback, only TgAb increased and FT4 decreased. CONCLUSIONS High-DBP novel exposure or removal from chronic high-DBP exposure could alter elements of the thyroid system, and most probably alters the peripheral T4 conversion to T3 and thyroid autoimmunity, consistent with thyroid disruption. After exposure removal, these trends were mostly reversed.

Diet and men's fertility: does diet affect sperm quality?

Male contribution to a couples fecundity is important, and identifying the dietary factors that can influence male fertility potential is of high importance. Despite this importance, there are currently no clear clinical guidelines for male patients seeking fertility treatment. In this review, we present the most up-to-date evidence about diet and male fertility in humans. We focus on the dietary factors necessary for production of healthy functioning sperm with high fertility potential. Based on this review, men may be encouraged to use antioxidant supplements and to follow dietary patterns favoring the consumption of seafood, poultry, nuts, whole grains, fruits, and vegetables. Evidence is strongest for recommending the use of antioxidant supplements to men in couples undergoing infertility treatment-although the specific antioxidants and doses remain unclear-and increasing consumption of omega-3 fatty acids from fish and nuts.