Longitudinal Investigation Of Fertility And The Environment Research Articles

Urinary phthalate metabolites and their mixtures are associated with advanced sperm epigenetic aging in a general population

IntroductionWe have recently shown that sperm epigenetic age (SEA), a surrogate measure of biological aging in sperm, is associated with couples’ time-to-pregnancy (TTP). Advanced SEA was also observed among smokers, suggesting its susceptibility to environmental exposures. Therefore, we assessed the association between urinary phthalate metabolites and SEA in male partners of couples planning to conceive among the general population. MethodThe Longitudinal Investigation of Fertility and the Environment (LIFE) Study was a prospective multi-site and general population cohort study of couples who were interested in becoming pregnant. Among male partners (n = 333), eleven urinary phthalate metabolites were measured and SEA was previously developed using Super Learner ensemble algorithm. Multivariable linear regression was used to evaluate associations of SEA with individual metabolites. Bayesian kernel machine regression (BKMR), quantile g-computation (qgcomp) and weighted quantile sum (WQS) models were used for mixture analyses. Covariates included were BMI, cotinine, race and urinary creatinine. ResultIn the single metabolite multivariate analyses, nine (82%) phthalate metabolites displayed positive trends with SEA (range: 0.05–0.47 years). Of these metabolites, advanced SEA was significantly associated with interquartile range increases in exposure of three phthalates [MEHHP (β = 0.23, 95% CI: 0.03, 0.43, p = 0.03), MMP (β = 0.24, 95% CI: 0.01, 0.47, p = 0.04), and MiBP (β = 0.47, 95% CI: 0.14, 0.81, p = 0.01)]. Additionally, in BKMR and qgcomp (p = 0.06), but not WQS models, phthalate mixtures showed an overall positive trend with SEA, with MiBP, MMP and MBzP as major drivers of the mixture effects. ConclusionThis is the first study that combined single exposure and mixture models to associate male phthalate exposures with advanced epigenetic aging of sperm in men planning to conceive among the general population. Our findings suggest that phthalate exposure may contribute to the acceleration of biological aging of sperm.

A Bayesian multi-dimensional couple-based latent risk model with an application to infertility.

Motivated by the Longitudinal Investigation of Fertility and the Environment (LIFE) Study that investigated the association between exposure to a large number of environmental pollutants and human reproductive outcomes, we propose a joint latent risk class modeling framework with an interaction between female and male partners of a couple. This formulation introduces a dependence structure between the chemical patterns within a couple and between the chemical patterns and the risk of infertility. The specification of an interaction enables the interplay between the female and male's chemical patterns on the risk of infertility in a parsimonious way. We took a Bayesian perspective to inference and used Markov chain Monte Carlo algorithms to obtain posterior estimates of model parameters. We conducted simulations to examine the performance of the estimation approach. Using the LIFE Study dataset, we found that in addition to the effect of PCB exposures on females, the male partners' PCB exposures play an important role in determining risk of infertility. Further, this risk is subadditive in the sense that there is likely a ceiling effect which limits the probability of infertility when both partners of the couple are at high risk.

Biomarkers of preconception stress and the incidence of pregnancy loss.

Are biomarkers of preconception stress associated with pregnancy loss? Preconception stress, as measured by basal salivary cortisol and alpha-amylase concentrations, is not associated with pregnancy loss. Many studies, most of which have been retrospective, have identified an association between stressful life events and perceived stress and miscarriage. A prospective pregnancy study with preconception enrollment was conducted between 2005 and 2009. Among the 344 women who became pregnant during the Longitudinal Investigation of Fertility and the Environment (LIFE) study, 337 (98%) had salivary biomarker data for analysis. Couples planning pregnancy were followed for up to 12 months as they tried to become pregnant and through pregnancy if it occurred. Participating women collected a basal saliva sample on the morning following enrollment and a second on the morning following their next menses to measure cortisol and alpha-amylase, biomarkers of stress. Women used home pregnancy tests on the day of expected menses. A pregnancy loss was defined as a negative pregnancy test following a positive pregnancy test, the onset of menses, or for pregnancies that survived to clinical recognition, recognition of the loss by a healthcare provider. Among the 337 couples, the median age of female and male partners was 29 and 31 years, respectively. Most of the women were non-Hispanic white (83%) and highly educated. There were 97 pregnancy losses reported among the 337 pregnancies. The median gestational age at loss was 6 weeks 5 days with only two losses occurring in the second trimester. Using Cox proportional hazards models, we found no clear pattern of association between two preconceptional biomarkers of stress (salivary cortisol and alpha-amylase concentrations) modeled both continuously or in tertiles and incident pregnancy loss after adjustment for confounders. Our prior work suggests that women enrolled in the LIFE Study had lower stress levels than women in the general population. Owing to concerns regarding participant burden, we were unable to collect serial saliva measurements, which would have allowed us to examine the association between stress in early pregnancy and pregnancy loss. Further, with regard to the measurement of perceived stress, the Cohen's Perceived Stress Scale was only administered at baseline. While every attempt was made to ensure diversity in the cohort, non-Hispanic white women were over-represented, therefore it is possible that the results might not be generalizable to all women. In one of the largest studies in the USA to prospectively capture data on the incidence of early pregnancy loss, we found no clear association between two biomarkers of preconception stress (measured in saliva) and pregnancy loss. This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355, N01-HD-3-3356, N01-HD-3358). There are no conflicts of interest to declare. Not applicable.

Maternal and paternal serum concentrations of persistent organic pollutants and the secondary sex ratio: A population-based preconception cohort study

Recent declines in the secondary sex ratio (SSR), defined as the ratio of males to females at birth, in some industrialized countries may be attributed to exposure to environmental toxicants such as persistent organic pollutants (POPs). This study aimed to evaluate the association of couples’ preconception exposure to POPs with the SSR. The study cohort comprised 235 couples who were enrolled in the Longitudinal Investigation of Fertility and the Environment (LIFE) Study between 2005 and 2009 prior to conception and prospectively followed through delivery of a singleton birth. Upon enrollment, couples’ serum concentrations (ng/g) were measured for 9 organochlorine pesticides, 1 polybrominated biphenyl, 10 polybrominated diphenyl ethers, and 36 polychlorinated biphenyls (PCBs). Birth outcome data including infant sex were collected upon delivery. Modified Poisson regression models were used to estimate the relative risks (RRs) and 95% confidence intervals (CIs) of a male birth for each chemical. Of the 56 POPs examined, maternal PCB 128 and paternal hexachlorobenzene were significantly associated with a female excess (RRs, 0.75 [95% CI, 0.60–0.94] and 0.81 [95% CI, 0.68–0.97] per 1SD increase in log-transformed serum chemical concentrations, respectively), whereas maternal mirex and paternal PCB 128 and p,p′-dichlorodiphenyldichloroethylene were significantly associated with a male excess (RR range, 1.10–1.22 per 1SD increase in log-transformed serum chemical concentrations). After adjusting for multiple comparisons, only maternal mirex remained significantly associated with the SSR. This exploratory study on multiple classes of POPs demonstrated no conclusive evidence on the association between parental preconception exposure to POPs and the SSR.

Semen quality and pregnancy loss in a contemporary cohort of couples recruited before conception: data from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study

To study the relationship between semen quality and pregnancy loss in a cohort of couples attempting to conceive. Observational prospective cohort. Not applicable. Three hundred and forty-four couples with a singleton pregnancy observed daily through 7 postconception weeks of gestation. None. Association between semen quality and pregnancy loss. Ninety-eight (28%) of the couples experienced a pregnancy loss after singleton pregnancy. No differences were observed in semen volume, sperm concentration, total sperm count, sperm viability, or sperm morphology (World Health Organization [WHO] and strict criteria) by couple's pregnancy loss status irrespective of whether they were analyzed continuously or as dichotomous variables per the WHO 5th edition semen criteria. A dichotomous DNA fragmentation measure of ≥30% was statistically significantly associated with pregnancy loss. No association was identified with other sperm morphometric or movement measures. Of the 70 couples who re-enrolled after a pregnancy loss, 14 experienced a second loss. Similar findings were identified when examining semen quality from couples with recurrent pregnancy loss. Although a few trends were identified (e.g., DNA fragmentation), general semen parameters seemed to have little relation with risk of pregnancy loss or recurrent pregnancy loss at the population level. However, given that 30% of pregnancies end in miscarriage and half the fetal genome is paternal in origin, the findings await corroboration.

Male birthweight, semen quality and birth outcomes.

What are the relations among birthweight (BW), semen parameters and birth outcomes in a population-based sample? BW is unrelated to semen parameters, which are in turn unrelated to birth outcomes. In clinical settings, there has been suggestion that semen parameters are related to BW when comparing fertile and infertile men; however, findings have been less clear in more general populations. Questionnaire data and semen samples were collected at baseline from 427 male participants of the population-based Longitudinal Investigation of Fertility and the Environment (LIFE) prospective cohort study from 2005 to 2009, who were followed prospectively to assess pregnancy outcomes among 226 singleton births. Men of at least 18 years of age who were married or in a committed relationship and trying to conceive were eligible for participation; physician-diagnosed infertility was an exclusion criterion. Participants were recruited from two geographic areas and semen samples were analyzed for 34 quality parameters categorized as general, motility, morphology, sperm head and sperm chromatin structure using methods including computer-aided semen analysis integrated visual optical system and sperm chromatin structure assay. Linear and mixed models were used for statistical analysis of the relations between men's BW, semen parameters, and BW, gestational age at delivery, birth length, head circumference and ponderal index of singleton births. No association was observed between male BW and semen parameters or birth outcomes. Few associations were observed between semen parameters and birth outcomes, and the observed statistically significant associations were isolated and without a consistent pattern that would suggest an association between BW and birth outcomes. Men's BW was self-reported and may be subject to some imprecision. Semen analysis was performed the day after collection, an approach that impacts the assessment of motility and that may limit inference from our analyses of motility measures. In addition, inclusion criteria for selection into the cohort limits generalizability to generally healthy couples trying to conceive and without known subfertility. Despite suggestions from prior studies of male in utero exposures impacting BW and male reproductive health, there appears to be little support for such relations in this generally healthy population. Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N01-HD-3-3355, N01-HD-3-3356 and NOH-HD-3-3358). The authors report no competing interests, and a Memo of Understanding with the National Institute of Occupational Safety and Health (NIOSH) for semen analysis. Not applicable.

Paternal exposures to environmental chemicals and time-to-pregnancy: overview of results from the LIFE study.

Published findings from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study regarding the relation between environmental chemicals and couple fecundity, as measured by time-to-pregnancy (TTP), are reviewed with a particular focus on role of the male partner. The LIFE Study recruited 501 couples from 16 counties in two U.S. states upon discontinuing contraception for purposes of becoming pregnant. Upon enrollment, couples provided a blood and urine sample for the quantification of persistent and non-persistent environmental chemicals, respectively, and then completed daily journals until pregnant or up to one year of trying. Female partners used fertility monitors to aid the timing of intercourse relative to ovulation, and digital home pregnancy test kits on the day of expected menses. Chemical classes included: metals, persistent organic pollutants, environmental phenols, and phthalates that were quantified using inductively coupled plasma mass spectrometry or isotope dilution high-resolution or tandem mass spectrometry. Time-to-pregnancy (TTP) was defined as the number of prospectively observed menstrual cycles required for pregnancy. Fecundability odds ratios (FORs) and 95% confidence intervals (CIs) were estimated for each chemical and partner after adjusting for potential confounders and accounting for right censoring and time off contraception. FORs<1 are suggestive of diminished fecundity or a longer TTP. Significant reductions (ranging from 17-31%) in couple fecundity were observed for male partners' concentration of lead (0.83; 0.70, 0.98), 2,2',4,4'-tetrahydroxybenzophenone (0.69; 0.49, 0.97), monobenzyl (0.80; 0.67, 0.97), and monomethyl (0.81; 0.70, 0.94) phthalates after adjusting for the female partners' concentrations. Seven PCB congeners quantified in men's serum were associated with a 17-29% reduction in couple fecundity. Our findings underscore the importance of a couple-based exposure design, inclusive of the male partner, when assessing couple-dependent outcomes such as TTP to avoid misinterpretation of results based only upon the female partner.

Couples' urinary concentrations of benzophenone-type ultraviolet filters and the secondary sex ratio

The secondary sex ratio (SSR), defined as the ratio of males to females at birth, has been investigated in relation to endocrine disruptors to search for environmental toxicants perturbing human sex selection. Benzophenone (BP)-type ultraviolet (UV) filters, which are used in sunscreens and personal care products, have been reported to exert estrogenic and anti-androgenic activities. This study aimed to evaluate the association between maternal, paternal, and couple urinary concentrations of BP-type UV filters and the SSR, given the absence of previous investigation. The study cohort comprised 220 couples who were enrolled in the Longitudinal Investigation of Fertility and the Environment (LIFE) Study between 2005 and 2009 prior to conception and who had a singleton birth during the follow-up period. Couples' urinary concentrations of five BP-type UV filters (ng/mL) were measured using triple-quadrupole tandem mass spectrometry: 2,4-dihydroxybenzophenone (BP-1), 2,2′,4,4′-tetrahydroxybenzophenone (BP-2), 2-hydroxy-4-methoxybenzophenone (BP-3), 2,2′-dihydroxy-4-methoxybenzophenone (BP-8), and 4-hydroxybenzophenone (4-OH-BP). Modified Poisson regression models were used to estimate the relative risks (RRs) of a male birth for each BP-type UV filter, after adjusting for potential confounders. When maternal and paternal urinary BP-type UV filter concentrations were modeled jointly, both maternal BP-2 (2nd vs 1st tertile, RR, 0.62, 95% confidence interval [CI], 0.43–0.91) and paternal BP-2 (3rd vs 1st tertile, RR, 0.67, 95% CI, 0.45–0.99; p-trend, 0.04) were significantly associated with an excess of female births. Contrarily, maternal 4-OH-BP was significantly associated with an excess of male births (2nd vs 1st tertile, RR, 1.87, 95% CI, 1.27–2.74; 3rd vs 1st tertile, RR, 1.80, 95% CI, 1.13–2.87; p-trend, 0.02). Our findings provide the first evidence suggesting that BP-type UV filters may affect the SSR. However, future corroboration is needed, given the exploratory design of this study.

Relationship between physical occupational exposures and health on semen quality: data from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study

To study the relationship among occupation, health, and semen quality in a cohort of men attempting to conceive. Observational prospective cohort. Not applicable. A total of 501 couples discontinuing contraception were followed for 1year while trying to conceive; 473 men (94%) provided one semen sample, and 80% provided a second sample. None. Semen data obtained through at-home semen collection with next-day analysis/quantification. In all, complete data were available for 456 men, with a mean age of 31.8years. Work-related heavy exertion was consistently associated with lower semen concentration and total sperm count. Thirteen percent of men who reported heavy exertion displayed oligospermia, compared with 6% who did not report workplace exertion. Shift work, night work, vibration, noise, heat, and prolonged sitting were not associated with semen quality. Men with high blood pressure had significantly lower strict morphology scores compared with normotensive men (17% vs. 21%). In contrast, hyperlipidemia, diabetes, and composite of total comorbidities were not associated with semen quality. The number of medications a man was taking as a proxy of health status was associated with semen quality. There was a negative association between number of medications and sperm count. A negative relationship among occupational exertion, hypertension, and the number of medications with semen quality was identified. As these are potentially modifiable factors, further research should determine whether treatment or cessation may improve male fecundity.

Birth outcomes and background exposures to select elements, the Longitudinal Investigation of Fertility and the Environment (LIFE)

Evidence suggests that trace exposures to select elements may increase the risk for adverse birth outcomes. To investigate further, we used multiple regression to assess associations between preconception parental exposures to Pb, Cd, and total Hg in blood, and 21 elements in urine, with n=235 singleton birth outcomes, adjusted for confounders and partner's exposure. Earlier gestational age at delivery (GA) was associated with higher tertiles of urine maternal W (−1.22 days) and paternal U (−1.07 days), but GA was later for higher tertiles of maternal (+1.11 days) and paternal (+1.30 days) blood Hg. Additional analysis indicated shorter GA associated with higher paternal urine Ba, W, and U, and with higher maternal blood Pb for boys, but GA was longer in association with higher maternal urine Cr. Birth weight (BW) was lower for higher tertiles of paternal urine Cs (−237.85g), U (−187.34g), and Zn (−209.08g), and for higher continuous Cr (P=0.021). In contrast, BW was higher for higher tertiles of paternal urine As (+194.71g) and counterintuitively for maternal blood Cd (+178.52g). Birth length (BL) was shorter for higher tertiles of urine maternal W (−1.22cm) and paternal U (−1.10cm). Yet, higher tertiles of maternal (+1.11cm) and paternal (+1.30) blood Hg were associated with longer BL. Head circumference at delivery was lower for higher tertiles of paternal urine U (−0.83cm), and for higher continuous Mo in boys (−0.57cm). Overall, associations were most consistently indicated for GA and measures of birth size with urine W and U, and paternal exposures were more frequently associated than maternal. Though limited by several factors, ours is the largest multi-element investigation of prospective couple-level trace exposures and birth outcomes to date; the novel observations for W and U merit further investigation.

Couples' urinary bisphenol A and phthalate metabolite concentrations and the secondary sex ratio

With limited research focusing on non-persistent chemicals as exogenous factors affecting human sex selection, this study aimed to evaluate the association of urinary bisphenol A (BPA) and phthalate metabolite concentrations with the secondary sex ratio (SSR), defined as the ratio of male to female live births. The current analysis is limited to singleton live births (n=220, 43.9%) from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study, in which couples discontinuing contraception with the intention of becoming pregnant were enrolled and followed while trying for pregnancy and through delivery for those achieving pregnancy. Using modified Poisson regression models accounting for potential confounders, we estimated the relative risks (RRs) of a male birth per standard deviation change in the log-transformed maternal, paternal, and couple urinary BPA and 14 phthalate metabolite concentrations (ng/mL) measured upon enrollment. When maternal and paternal chemical concentrations were modeled jointly, paternal BPA (RR, 0.77; 95% confidence interval [CI], 0.62–0.95) and mono-isobutyl phthalate (RR, 0.82; 95% CI, 0.67–1.00) were significantly associated with a female excess. Contrarily, maternal BPA (RR, 1.16; 95% CI, 1.03–1.31), mono-isobutyl phthalate (RR, 1.28; 95% CI, 1.06–1.54), mono-benzyl phthalate (RR, 1.31; 95% CI, 1.08–1.58), and mono-n-butyl phthalate (RR, 1.24; 95% CI, 1.01–1.51) were significantly associated with a male excess. These findings underscore varying patterns for the SSR in relation to parental exposures. Given the absence of previous investigation, these partner-specific associations of non-persistent chemicals with the SSR need future corroboration.

Urinary concentrations of benzophenone-type ultraviolet radiation filters and couples' fecundity.

Concern has arisen about benzophenone (BP) ultraviolet (UV) radiation filters, given their use in sunscreen and personal-care products and their reported estrogenic and antiandrogenic activity. We recruited 501 couples who were discontinuing use of contraceptives in order to become pregnant for the Longitudinal Investigation of Fertility and the Environment (LIFE) Study (Michigan and Texas, 2005-2009). Couples provided urine specimens and completed daily journals until they either achieved pregnancy or had tried for 12 months. Women used fertility monitors to time sexual intercourse and digital pregnancy tests. Urinary concentrations of 5 UV filters (ng/mL) were determined using triple-quadrupole mass spectrometry: 2,4-dihydroxybenzophenone (also called BP-1); 2,2',4,4'-tetrahydroxybenzophenone (BP-2); 2-hydroxy-4-methoxybenzophenone (BP-3); 2,2'-dihydroxy-4-methoxybenzophenone (BP-8); and 4-hydroxybenzophenone. Fecundability odds ratios were estimated for each UV filter (dichotomized at the 75th percentile) and adjusted for age, creatinine concentration, body mass index (weight (kg)/height (m)(2)), cotinine concentration, season, and site, while accounting for time off contraception. Separate models were fitted for each UV filter and partner; final models included partners' concentrations. Male partners' concentrations of BP-2 and 4-hydroxybenzophenone were associated with reduced fecundity in adjusted models (fecundability odds ratio (FOR) = 0.69 (95% confidence interval (CI): 0.50, 0.95) and FOR = 0.74 (95% CI: 0.54, 1.00), respectively). In models adjusting for both partners' concentrations, male BP-2 concentration remained associated with reduced fecundity (FOR = 0.69, 95% CI: 0.49, 0.97). These data suggest that male exposure to select UV filters may diminish couples' fecundity, resulting in a longer time to pregnancy.

Urinary Bisphenol A and Phthalate Metabolite Concentrations and the Secondary Sex Ratio: The Life Study

Urinary Bisphenol A and Phthalate Metabolite Concentrations and the Secondary Sex Ratio: The Life Study

Urinary bisphenol A, phthalates, and couple fecundity: the Longitudinal Investigation of Fertility and the Environment (LIFE) Study

To assess the relationship between environmental chemicals and couple fecundity or time to pregnancy (TTP). Prospective cohort. Communities of targeted populations with reported exposure. 501 couples recruited upon discontinuing contraception to become pregnant, 2005-2009. None. Fecundability odds ratios (FORs) and 95% confidence intervals (CIs) estimated for each partner's chemical concentrations adjusted for age, body mass index, cotinine, creatinine, and research site while accounting for time off contraception. Couples completed interviews and anthropometric assessments and provided the urine specimens for quantification of bisphenol A (BPA) and 14 phthalate metabolites, which were measured using high-performance liquid chromatography with electrospray triple-quadrupole mass spectrometer. Women recorded menstruation and pregnancy test results in daily journals. Couples were evaluated until a positive human-chorionic gonadotropin pregnancy test or 12 cycles without pregnancy. Neither female nor male BPA concentration was associated with TTP (FOR 0.98; 95% CI, 0.86, 1.13 and FOR 1.04; 95% CI, 0.91, 1.18, respectively). Men's urinary concentrations of monomethyl, mono-n-butyl, and monobenzyl phthalates were associated with a longer TTP (FOR 0.80; 95% CI, 0.70, 0.93; FOR 0.82, 95% CI, 0.70, 0.97; and FOR 0.77, 95% CI, 0.65 0.92, respectively). Select male but not female phthalate exposures were associated with an approximately 20% reduction in fecundity, underscoring the importance of assessing both partners' exposure to minimize erroneous conclusions.

The relationship between male BMI and waist circumference on semen quality: data from the LIFE study

What is the relationship between body size, physical activity and semen parameters among male partners of couples attempting to become pregnant? Overweight and obesity are associated with a higher prevalence of low ejaculate volume, sperm concentration and total sperm count. Higher BMI is associated with impaired semen parameters, while increasing waist circumference (WC) is also associated with impaired semen parameters in infertile men. Data from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study were utilized. The LIFE study is a population-based prospective cohort of 501 couples attempting to conceive in two geographic areas (Texas and Michigan, USA) recruited in 2005-2009. Couples were recruited from four counties in Michigan and 12 counties in Texas to ensure a range of environmental exposures and lifestyle characteristics. In person interviews were conducted to ascertain demographic, health and reproductive histories followed by anthropometric assessment. We categorized BMI (kg/m(2)) as <25.0 (underweight and normal), 25.0-29.9 (overweight) 30.0-34.9 (obese, class I) and ≥35 (obese, class II) for analysis. Data were available for analysis in 468 men (93% participation), with a mean ± SD age of 31.8 ± 4.8 years, BMI of 29.8 ± 5.6 kg/m(2) and WC of 100.8 ± 14.2 cm. The majority of the cohort (82%) was overweight or obese with 58% reporting physical activity <1 time/week. The median sperm concentration for the men in the cohort was 60.2 M/ml with 8.6% having oligospermia (<15 M/ml). When examining semen parameters, ejaculate volume showed a linear decline with increasing BMI and WC (P < 0.01). Similarly, the total sperm count showed a negative linear association with WC (P < 0.01). No significant relationship was seen between body size (i.e. BMI or WC) and semen concentration, motility, vitality, morphology or DNA fragmentation index. The percentage of men with abnormal volume, concentration and total sperm increased with increasing body size (P < 0.05). No relationship between physical activity and semen parameters was identified. Our cohort was largely overweight and sedentary, which may result in limited external validity, i.e. generalizability. The lack of physical activity did preclude examination of exercise more frequently than once per week, thus our ability to examine more active individuals is limited. Body size (as measured by BMI or WC) is negatively associated with semen parameters with little influence of physical activity. Our findings are the first showing a relationship between WC and semen parameters in a sample of men without known infertility. Given the worldwide obesity epidemic, further study of the role of weight loss to improve semen parameters is warranted. Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contracts #N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). There are no competing interests.