The molecular effects of intermediate and long-term exposure to air pollution and temperature, such as those on extracellular microRNA (ex-miRNA) are not well understood but may have clinical ...consequences.
To assess the association between exposure to ambient air pollution and temperature and ex-miRNA profiles.
Our study population consisted of 734 participants in the Normative Aging Study (NAS) between 1999 and 2015. We used high-resolution models to estimate four-week, eight-week, twelve-week, six-month, and one-year moving averages of PM2.5, O3, NO2, and ambient temperature based on geo-coded residential addresses. The outcome of interest was the extracellular microRNA (ex-miRNA) profile of each participant over time. We used a longitudinal quantile regression approach to estimate the association between the exposures and each ex-miRNA. Results were corrected for multiple comparisons and ex-miRNAs that were still significantly associated with the exposures were further analyzed using KEGG pathway analysis and Ingenuity Pathway Analysis.
We found 151 significant associations between levels of PM2.5, O3, NO2, and ambient temperature and 82 unique ex-miRNAs across multiple quantiles. Most of the significant results were associations with intermediate-term exposure to O3, long-term exposure to PM2.5, and both intermediate and long-term exposure to ambient temperature. The exposures were most often associated with the 75th and 90th percentile of the outcomes. Pathway analyses of significant ex-miRNAs revealed their involvement in biological pathways involving cell function and communication as well as clinical diseases such as cardiovascular disease, respiratory disease, and neurological disease.
Our results show that intermediate and long-term exposure to all our exposures of interest were associated with changes in the ex-miRNA profile of study participants. Further studies on environmental risk factors and ex-miRNAs are warranted.
•Extracellular microRNA profiles may change in response to environmental stressors.•Exposure to O3, PM2.5, and temperature are associated with microRNA changes.•Significant changes were mostly seen in higher quantiles of microRNA levels.•Changes in the extracellular microRNA profile may have clinical consequences.
BACKGROUND:Randomized trials of supplementation with antioxidant mixtures during infertility treatment show no benefit on pregnancy or live birth rate. However, the roles of individual antioxidants ...are poorly understood. We examined the association of baseline intake of vitamins A, C, E, and carotenoids with outcomes of assisted reproductive technologies (ARTs).
METHODS:We followed 349 women undergoing a total of 588 ART cycles for infertility treatment at the Massachusetts General Hospital. We assessed antioxidant intakes from food and supplements before treatment using a validated food frequency questionnaire. We used generalized linear mixed models to account for multiple ART cycles per woman while adjusting for confounding.
RESULTS:Mean (SD) age and body mass index were 35.1 years (4.0 years) and 24.1 kg/m (4.3 kg/m), respectively. Total intake of vitamins A, C, and E was not associated with the probability of live birth. Women in the highest intake category of β-carotene from foods had a lower probability of live birth than women in the lowest intake quartile (50% vs. 22%; P trend = 0.03); for lutein and zeaxanthin, the probability for the highest intake group was 44% vs. 28% for the lowest. Intake of β-carotene from supplements and intakes of retinol and all other carotenoids were unrelated to live birth rates.
CONCLUSIONS:We found unexpected inverse associations of β-carotene intake from foods and of lutein and zeaxanthin intake with live birth rates. Within the observed intake ranges, total consumption of vitamins A, C, and E before starting infertility treatment with ART was not associated with live birth rates.
Randomized clinical trials show that men's use of antioxidant supplements during infertility treatment may improve clinical outcomes. However, important limitations in the design of most trials make ...it difficult to draw firm conclusions on their findings.
We examined whether men's intake of antioxidants and biologically related compounds without direct antioxidant capacity is associated with outcomes of assisted reproductive technologies (ARTs).
We conducted a prospective cohort study of men in couples who underwent infertility treatment with ART using their own gametes between 2007 and 2017. We followed 171 couples who presented at Massachusetts General Hospital Fertility Center and underwent 294 autologous ART cycles for infertility treatment. Diet was assessed in both partners using an FFQ. The primary study outcome was the probability of achieving a live birth as a result of infertility treatment. Secondary outcomes were fertilization, implantation, and clinical pregnancy rates. Generalized linear mixed models with random intercepts were fitted to account for multiple ART cycles per woman while adjusting for confounding.
Men's vitamin C intake was positively associated with fertilization rate. The adjusted fertilization rate (95% CI) for couples in the lowest and highest quartiles of men's vitamin C intake were 69% (61–76%) and 81% (74–86%) (P-trend = 0.02). Men's β-carotene intake was positively associated with fertilization rate in intracytoplasmic sperm injection cycles but not in conventional in vitro fertilization cycles (P-interaction = 0.01). Men's α-carotene intake was inversely related to the probability of live birth. The adjusted probabilities of live birth for men in the lowest and highest quartiles of α-carotene intake were 43% (28–60%) and 22% (12–36%), respectively.
Men's intake of vitamin C and β-carotene is positively related to fertilization rate but this does not translate into higher pregnancy or live birth rates in couples undergoing infertility treatment.
Studies in rodents have shown that paternal folate intake prior to conception is associated with pregnancy and offspring outcomes. The aim of this study was to assess whether those associations might ...apply to humans as well.
Between 2007 and 2017, the study prospectively analysed data from 108 couples participating in a preconception cohort of couples undergoing fertility treatment using their own gametes, whose treatment resulted in 113 pregnancies during the course of the study. Paternal and maternal preconception folate intake was assessed using a validated food frequency questionnaire. Linear mixed models were used to assess whether paternal preconception folate intake was associated with gestational age at delivery and gestational age-specific birthweight, while accounting for correlated data and potential confounders.
In a multivariable-adjusted model, a 400 μg/day increase in preconception paternal folate intake was associated with a 2.6-day longer gestation (95% confidence interval 0.8–4.3) after adjusting for potential confounders, including maternal folate intake. Similar associations were found for folate from food and supplements. Maternal folate intake was not associated with gestational age at delivery. Neither paternal nor maternal folate intake was associated with gestational-age-specific birthweight.
Higher paternal preconception folate intake was associated with slightly longer gestation among live births achieved through assisted reproduction. The results suggest that preconception exposures of the father may have an impact on the health of his offspring, and therefore that preconception care should shift from a woman-centric to a couple-based approach.
To examine the association betweenantineoplastic drug (AD) handling and risk of miscarriage.
Nurses’ Health Study-3 participants self-reported AD administration and engineering controls (ECs) and ...personal protective equipment (PPE) use at baseline. We estimated the hazard ratio (HR) of miscarriage in relation to baseline AD handling using multivariable Cox proportional regression.
Overall, 2440 nurses reported 3327 pregnancies, with 550 (17%) ended in miscarriages. Twelve percent of nurses self-reported currently handling AD and 28% previously handling AD. Compared with nurses who never handled AD, nurses who handled AD at baseline had an adjusted HR of miscarriage of 1.26 (95% confidence interval CI, 0.97–1.64). This association was stronger after 12-weeks gestation (HR=2.39 95% CI, 1.13–5.07). Nurses who did not always use gloves had HR of 1.51 (95% CI, 0.91–2.51) compared with 1.19 (95% CI, 0.89–1.60) for those always using gloves; nurses who did not always use gowns had HR of 1.32 (95% CI, 0.95–1.83) compared with 1.19 (95% CI, 0.81–1.75) for nurses always using gowns.
We observed a suggestive association between AD handling and miscarriage, particularly among nurses who did not consistently use PPE and EC with stronger associations for second trimester losses.
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.
La recherche sur les perturbateurs endocriniens (PE) s’est développée avec l’apport de différentes disciplines. Dans cette pluridisciplinarité, l’épidémiologie a un rôle à jouer pour éclairer la pertinence des mécanismes d’action de PE identifiés dans d’autres modèles, caractériser les relations dose–réponse, l’impact sanitaire à l’échelle de la population (nombre de cas attribuables à l’exposition aux PE et coût économique associé) et l’efficacité de mesures pour limiter l’exposition. Nous présentons les outils épidémiologiques permettant de tirer des conclusions valides pour l’humain sur les substances suspectées d’être des PE. Une spécificité de l’épidémiologie est sa nature essentiellement observationnelle, nécessitant une attention particulière dans le contrôle des biais de confusion. Un autre point central est lié à la nature peu persistante dans l’organisme de beaucoup de PE potentiels. Des approches, s’appuyant sur un recueil répété d’échantillons biologiques chez chaque sujet, permettent de limiter l’erreur de mesure et les biais pouvant en résulter. Du point de vue du design d’étude, l’approche centrale pour la problématique des PE non persistants est celle de la cohorte couple–enfants. Ces cohortes peuvent s’appuyer sur les développements de la biologie moléculaire pour caractériser exposition et mécanismes intermédiaires, ce qui correspond à l’avènement de l’épidémiologie moléculaire, permettant des interactions plus fructueuses entre épidémiologie, toxicologie et biologie moléculaire.
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.
Taking advantage of differences in mesalamine formulations, we investigated whether high-DBP exposure from mesalamine medications was associated with decreased semen parameters.
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).
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.
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.
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•Mesalamine with coating containing dibutyl phthalate(DBP) impart high-DBP exposure.•Men newly exposed to DBP containing mesalamine had a reduction in semen quality.•The most robust effect of high-DBP exposure from mesalamine was on sperm motility.•High-DBP effect on sperm motility persisted for 4months after removing exposure.
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.
IMPORTANCE: Diet may play a role in testicular function, but data on how adherence to different diet patterns influences human testicular function are scarce. OBJECTIVE: To determine whether ...adherence to specific dietary patterns is associated with testicular function in young men. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included 2935 young Danish men unselected regarding fertility status who were enrolled from April 1, 2008, through May 31, 2017. Data were analyzed from July 1, 2017, to January 30, 2019. EXPOSURES: Dietary patterns identified with principal component analysis based on responses to a validated food frequency questionnaire. MAIN OUTCOMES AND MEASURES: Standard semen quality assessment; serum concentrations of testosterone, free testosterone, estradiol, inhibin B, follicle-stimulating hormone, luteinizing hormone, and sex hormone–binding globulin; and testicular volume measured with ultrasonography. RESULTS: Among the 2935 participants included in the analysis, median age was 19 (interquartile range, 19-20) years and 2290 (78.0%) had normal body mass index. The 4 dietary patterns identified included Western, prudent, open-sandwich (a traditional Danish eating pattern), and vegetarianlike. The greatest adherence to the prudent pattern was associated with the highest total sperm count (median, 167 95% CI, 146-183 million), followed by adherence to vegetarianlike (median, 151 95% CI, 134-168 million) and open-sandwich (median, 146 95% CI, 131-163 million) patterns. Adherence to the Western pattern was associated with the lowest total sperm count (median, 122 95% CI, 109-138 million), which was significantly lower than sperm count in the other 3 diet patterns. After adjusting for confounders, the median total sperm count for men in the highest quintile of adherence to the Western pattern was 26 million lower (95% CI, –42 to –9 million) than for men in the lowest quintile of adherence to this pattern. Conversely, the median total sperm count of men in the highest quintile of adherence to the prudent pattern was 43 million (95% CI, 23-63 million) higher than that of men in the lowest quintile. Men with the highest adherence to the Western pattern had a lower median ratio of inhibin B to follicle-stimulating hormone (–12 95% CI, –20 to –3) and higher median ratio of free testosterone to luteinizing hormone (10 95% CI, 2-19) compared with men with lowest adherence to this pattern. CONCLUSIONS AND RELEVANCE: In this cross-sectional study, adherence to generally healthy diet patterns was associated with better semen quality, with potentially more favorable fertility potential among adult men.
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