John D. Meeker

Altered Semen Quality in Relation to Urinary Concentrations of Phthalate Monoester and Oxidative Metabolites

Background: Phthalates are multifunctional chemicals used in a variety of consumer, medical, and personal care products. Previously, we reported dose–response associations of decreased semen quality with urinary concentrations of monobutyl phthalate (MBP) and monobenzyl (MBzP) phthalate, which are metabolites of dibutyl phthalate and butylbenzyl phthalate, respectively. The present study extends our work in a larger sample of men and includes measurements of di(2-ethylhexyl) phthalate (DEHP) oxidative metabolites. Methods: Between January 2000 and May 2004, we recruited 463 male partners of subfertile couples who presented for semen analysis to the Massachusetts General Hospital. Semen parameters were dichotomized based on World Health Organization reference values for sperm concentration (<20 million/mL) and motility (<50% motile) and the Tygerberg Kruger Strict criteria for morphology (<4% normal). The comparison group was men with all 3 semen parameters above the reference values. In a single spot urine sample from each man, phthalate metabolites were measured using solid-phase extraction coupled to high-performance liquid chromatography isotope-dilution tandem mass spectrometry. Results: There were dose–response relationships of MBP with low sperm concentration (odds ratio per quartile adjusted for age, abstinence time, and smoking status = 1.00, 3.1, 2.5, 3.3; P for trend = 0.04) and motility (1.0, 1.5, 1.5, 1.8; P for trend = 0.04). There was suggestive evidence of an association between the highest MBzP quartile and low sperm concentration (1.00, 1.1, 1.1, 1.9; P for trend = 0.13). There were no relationships of monoethyl phthalate, monomethyl phthalate, and the DEHP metabolites with these semen parameters. Conclusion: The present study confirms previous results on the relationship of altered semen quality with exposure to MBP at general population levels. We did not find associations between semen parameters and 3 DEHP metabolites.

House Dust Concentrations of Organophosphate Flame Retardants in Relation to Hormone Levels and Semen Quality Parameters

Background Organophosphate (OP) compounds, such as tris(1,3-dichloro-2-propyl) phosphate (TDCPP) and triphenyl phosphate (TPP), are commonly used as additive flame retardants and plasticizers in a wide range of materials. Although widespread human exposure to OP flame retardants is likely, there is a lack of human and animal data on potential health effects. Objective We explored relationships of TDCPP and TPP concentrations in house dust with hormone levels and semen quality parameters. Methods We analyzed house dust from 50 men recruited through a U.S. infertility clinic for TDCPP and TPP. Relationships with reproductive and thyroid hormone levels, as well as semen quality parameters, were assessed using crude and multivariable linear regression. Results TDCPP and TPP were detected in 96% and 98% of samples, respectively, with widely varying concentrations up to 1.8 mg/g. In models adjusted for age and body mass index, an interquartile range (IQR) increase in TDCPP was associated with a 3% [95% confidence interval (CI), −5% to −1%) decline in free thyroxine and a 17% (95% CI, 4–32%) increase in prolactin. There was a suggestive inverse association between TDCPP and free androgen index that became less evident in adjusted models. In the adjusted models, an IQR increase in TPP was associated with a 10% (95% CI, 2–19%) increase in prolactin and a 19% (95% CI, −30% to −5%) decrease in sperm concentration. Conclusion OP flame retardants may be associated with altered hormone levels and decreased semen quality in men. More research on sources and levels of human exposure to OP flame retardants and associated health outcomes are needed.

Temporal variability of urinary phthalate metabolite levels in men of reproductive age

Phthalates are a family of multifunctional chemicals widely used in personal care and other consumer products. The ubiquitous use of phthalates results in human exposure through multiple sources and routes, including dietary ingestion, dermal absorption, inhalation, and parenteral exposure from medical devices containing phthalates. We explored the temporal variability over 3 months in urinary phthalate metabolite levels among 11 men who collected up to nine urine samples each during this time period. Eight phthalate metabolites were measured by solid-phase extraction–high-performance liquid chromatography–tandem mass spectrometry. Statistical analyses were performed to determine the between- and within-subject variance apportionment, and the sensitivity and specificity of a single urine sample to classify a subject’s 3-month average exposure. Five of the eight phthalates were frequently detected. Monoethyl phthalate (MEP) was detected in 100% of samples; monobutyl phthalate, monobenzyl phthalate, mono-2-ethylhexyl phthalate (MEHP), and monomethyl phthalate were detected in > 90% of samples. Although we found both substantial day-to-day and month-to-month variability in each individual’s urinary phthalate metabolite levels, a single urine sample was moderately predictive of each subject’s exposure over 3 months. The sensitivities ranged from 0.56 to 0.74. Both the degree of between- and within-subject variance and the predictive ability of a single urine sample differed among phthalate metabolites. In particular, a single urine sample was most predictive for MEP and least predictive for MEHP. These results suggest that the most efficient exposure assessment strategy for a particular study may depend on the phthalates of interest.

Phthalates and other additives in plastics: human exposure and associated health outcomes

Concern exists over whether additives in plastics to which most people are exposed, such as phthalates, bisphenol A or polybrominated diphenyl ethers, may cause harm to human health by altering endocrine function or through other biological mechanisms. Human data are limited compared with the large body of experimental evidence documenting reproductive or developmental toxicity in relation to these compounds. Here, we discuss the current state of human evidence, as well as future research trends and needs. Because exposure assessment is often a major weakness in epidemiological studies, and in utero exposures to reproductive or developmental toxicants are important, we also provide original data on maternal exposure to phthalates during and after pregnancy (n = 242). Phthalate metabolite concentrations in urine showed weak correlations between pre- and post-natal samples, though the strength of the relationship increased when duration between the two samples decreased. Phthalate metabolite levels also tended to be higher in post-natal samples. In conclusion, there is a great need for more human studies of adverse health effects associated with plastic additives. Recent advances in the measurement of exposure biomarkers hold much promise in improving the epidemiological data, but their utility must be understood to facilitate appropriate study design.

Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic

OBJECTIVE To examine the association between body weight and measures of male reproductive potential. DESIGN Cross-sectional study. SETTING Fertility clinic in an academic medical center. PATIENT(S) Four hundred eighty-three male partners of subfertile couples. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Standard semen analysis, sperm DNA fragmentation, and serum levels of reproductive hormones. RESULT(S) As expected, body mass index (BMI) was positively related to estradiol levels and inversely related to total testosterone and sex hormone-binding glogulin (SHBG) levels. There was also a strong inverse relation between BMI and inhibin B levels and a lower testosterone:LH ratio among men with a BMI > or = 35 kg/m(2). Body mass index was unrelated to sperm concentration, motility, or morphology. Ejaculate volume decreased steadily with increasing BMI levels. Further, men with BMI > or = 35 kg/m(2) had a lower total sperm count (concentration x volume) than normal weight men (adjusted difference in the median [95% confidence interval] = -86 x 10(6) sperm [-134, -37]). Sperm with high DNA damage were significantly more numerous in obese men than in normal-weight men. CONCLUSION(S) These data suggest that despite major differences in reproductive hormone levels with increasing body weight, only extreme levels of obesity may negatively influence male reproductive potential.

Semen quality and sperm DNA damage in relation to urinary bisphenol A among men from an infertility clinic.

Bisphenol A (BPA) impairs spermatogenesis in animals, but human studies are lacking. We measured urinary BPA concentrations, semen quality, and sperm DNA damage (comet assay) in 190 men recruited through an infertility clinic. BPA was detected in 89% of samples, with a median (interquartile range [IQR]) concentration of 1.3 (0.8-2.5) ng/mL. Urinary BPA concentration was associated with slightly elevated, though not statistically significant, odds for below reference sperm concentration, motility, and morphology. When modeled as continuous dependent variables, an IQR increase in urinary BPA concentration was associated with declines in sperm concentration, motility, and morphology of 23% (95%CI -40%, -0.3%), 7.5% (-17%, +1.5%), and 13% (-26%, -0.1%), respectively, along with a 10% (0.03%, 19%) increase in sperm DNA damage measured as the percentage of DNA in comet tail. In conclusion, urinary BPA may be associated with declined semen quality and increased sperm DNA damage, but confirmatory studies are needed.

Polybrominated diphenyl ether (PBDE) concentrations in house dust are related to hormone levels in men

Despite documented widespread human exposure to polybrominated diphenyl ethers (PBDEs) through dietary intake and contact with or inhalation of indoor dust, along with growing laboratory evidence for altered endocrine function following exposure, human studies of PBDE exposure and endocrine effects remain limited. We conducted a preliminary study within an ongoing study on the impact of environmental exposures on male reproductive health. We measured serum hormone levels and PBDE concentrations (BDE 47, 99 and 100) in house dust from 24 men recruited through a US infertility clinic. BDE 47 and 99 were detected in 100% of dust samples, and BDE 100 was detected in 67% of dust samples, at concentrations similar to those reported in previous US studies. In multivariable regression models adjusted for age and BMI, there was a statistically significant inverse relationship between dust PBDE concentrations and free androgen index. Dust PBDE concentrations were also strongly and inversely associated with luteinizing hormone (LH) and follicle stimulating hormone (FSH), and positively associated with inhibin B and sex hormone binding globulin (SHBG). Finally, consistent with limited recent human studies of adults, PBDEs were positively associated with free T4. In conclusion, the present study provides compelling evidence of altered hormone levels in relation to PBDE exposures estimated as concentrations in house dust, and that house dust is an important source of human PBDE exposure, but more research is urgently needed.

Temporal Variability and Predictors of Urinary Bisphenol A Concentrations in Men and Women

Background Bisphenol A (BPA) is used to manufacture polymeric materials, such as polycarbonate plastics, and is found in a variety of consumer products. Recent data show widespread BPA exposure among the U.S. population. Objective Our goal in the present study was to determine the temporal variability and predictors of BPA exposure. Methods We measured urinary concentrations of BPA among male and female patients from the Massachusetts General Hospital Fertility Center. Results Between 2004 and 2006, 217 urine samples were collected from 82 subjects: 45 women (145 samples) and 37 men (72 samples). Of these, 24 women and men were partners and contributed 42 pairs of samples collected on the same day. Ten women became pregnant during the follow-up period. Among the 217 urine samples, the median BPA concentration was 1.20 μg/L, ranging from below the limit of detection (0.4 μg/L) to 42.6 μg/L. Age, body mass index, and sex were not significant predictors of urinary BPA concentrations. BPA urinary concentrations among pregnant women were 26% higher (–26%, +115%) than those among the same women when not pregnant (p > 0.05). The urinary BPA concentrations of the female and male partner on the same day were correlated (r = 0.36; p = 0.02). The sensitivity of classifying a subject in the highest tertile using a single urine sample was 0.64. Conclusion We found a nonsignificant increase in urinary BPA concentrations in women while pregnant compared with nonpregnant samples from the same women. Samples collected from partners on the same day were correlated, suggesting shared sources of exposure. Finally, a single urine sample showed moderate sensitivity for predicting a subject’s tertile categorization.

Di(2-ethylhexyl) Phthalate Metabolites May Alter Thyroid Hormone Levels in Men

Background Phthalates are used extensively in many personal-care and consumer products, resulting in widespread nonoccupational human exposure through multiple routes and media. A limited number of animal studies suggest that exposure to phthalates may be associated with altered thyroid function, but human data are lacking. Methods Concurrent samples of urine and blood were collected from 408 men. We measured urinary concentrations of mono(2-ethylhexyl) phthalate (MEHP), the hydrolytic metabolite of di(2-ethylhexyl) phthalate (DEHP), and other phthalate monoester metabolites, along with serum levels of free thyroxine (T4), total triiodothyronine (T3), and thyroid-stimulating hormone (TSH). Oxidative metabolites of DEHP were measured in urine from only 208 of the men. Results We found an inverse association between MEHP urinary concentrations and free T4 and T3 serum levels, although the relationships did not appear to be linear when MEHP concentrations were categorized by quintiles. There was evidence of a plateau at the fourth quintile, which was associated with a 0.11 ng/dL decrease in free T4 [95% confidence interval (CI), –0.18 to –0.03] and a 0.05 ng/mL decrease in T3 (95% CI, –0.10 to 0.01) compared with the first (lowest) MEHP quintile. The inverse relationship between MEHP and free T4 remained when we adjusted for oxidative metabolite concentrations; this simultaneously demonstrated a suggestive positive association with free T4. Conclusions Urinary MEHP concentrations may be associated with altered free T4 and/or total T3 levels in adult men, but additional study is needed to confirm the observed findings. Future studies must also consider oxidative DEHP metabolites relative to MEHP as a potential marker of metabolic susceptibility to DEHP exposure.

Relationships between Polybrominated Diphenyl Ether Concentrations in House Dust and Serum

Polybrominated diphenyl ethers (PBDEs) have been measured in the home environment and in humans, but studies linking environmental levels to body burdens are limited. This study examines the relationship between PBDE concentrations in house dust and serum from adults residing in these homes. We measured PBDE concentrations in house dust from 50 homes and in serum of male-female couples from 12 of the homes. Detection rates, dust-serum, and within-matrix correlations varied by PBDE congener. There was a strong correlation (r = 0.65-0.89, p < 0.05) between dust and serum concentrations of several predominant PBDE congeners (BDE 47, 99, and 100). Dust and serum levels of BDE 153 were not correlated (r < 0.01). The correlation of dust and serum levels of BDE 209 could not be evaluated due to low detection rates of BDE 209 in serum. Serum concentrations of the sum of BDE 47, 99, and 100 were also strongly correlated within couples (r = 0.85, p = 0.0005). This study provides evidence that house dust is a primary exposure pathway of PBDEs and supports the use of dust PBDE concentrations as a marker for exposure to PBDE congeners other than BDE 153.