Ying-Jun Chen

Association of urinary metal levels with human semen quality: A cross-sectional study in China

BACKGROUND Exposure to metals, including essential and nonessential elements, has been linked to male reproductive health in animals. However, findings from human studies are inconsistent. OBJECTIVE To examine the associations between metal exposure at environmental levels and semen quality in a Chinese population by performing repeated measurements of urinary metals to estimate individual-level exposure. METHODS From March to June 2013, 1052 men seeking semen evaluation were recruited from the Reproductive Center of Tongji Hospital in Wuhan, China. Each man provided one semen sample and two urine sample. Semen quality parameters and urinary levels of 18 metals were determined. Associations between the urinary metal levels and semen quality parameters were assessed using confounder adjusted linear and logistic regressions. Restricted cubic spline analysis was performed to assess dose-response relationships between continuous metal measurements and outcomes. RESULTS Urinary levels of cadmium were significantly inversely associated with progressive sperm motility and total motility (both P<0.02) based on multivariable linear regression models, consistent with the trends of increased odds ratios for below-reference semen quality parameters observed in the logistic models (both P<0.05). Additionally, we found significant inverse associations of urinary molybdenum and lead with percentages of normal sperm morphology (both P<0.05). These associations remained suggestive or significant after adjustment for multiple testing. They were also robust to the simultaneous consideration of multiple metals, and curves of restricted cubic spline showed clear dose-response relationships. CONCLUSION Our findings suggest that environmental exposure to cadmium, molybdenum and lead may contribute to a decline in human semen quality.

Associations of urinary metal levels with serum hormones, spermatozoa apoptosis and sperm DNA damage in a Chinese population.

BACKGROUND Exposure to metals, including essential and nonessential elements, is widespread and may be associated with male reproductive health. OBJECTIVE To examine whether environmental exposure to metals contributes to reproductive hormone changes, spermatozoa apoptosis and sperm DNA damage in a Chinese population. METHODS Eighteen metals (aluminum, arsenic, antimony, chromium, cobalt, copper, cadmium, iron, lead, manganese, molybdenum, nickel, selenium, tin, tungsten, thallium, uranium and zinc) were analyzed in two urine samples collected a few hours apart from male partners of couples attending an infertility clinic. Multivariable linear regression models were used to assess the cross-sectional associations of average urinary metal levels with serum hormones (n=511), spermatozoa apoptosis measures (n=460) and sperm DNA damage parameters (n=516). RESULTS We found significant inverse dose-dependent trends of urinary tin quartiles with total testosterone (T), and tin, nickel, zinc and molybdenum with the ratio of total T to luteinizing hormone (total T/LH ratio) (all Ptrend<0.05). Additionally, we found significantly dose-dependent trends of increasing urinary manganese quartiles with increasing percentage of Annexin V+/PI- spermatozoa and increasing iron with decreasing percentage of PI+ spermatozoa (both Ptrend<0.05). These dose-dependent trends remained suggestive or significant after controlling for multiple testing and other metals, and they persisted when the metals were modeled as continuous variables in a cubic spline analysis. There were no significant associations between urinary metals and sperm DNA damage after adjustment for multiple testing. CONCLUSION Environmental exposure to tin, nickel, zinc and molybdenum may be associated decreased total T or total T/LH ratio; manganese may induce spermatozoa apoptosis, while iron may be important for living spermatozoa. However, additional prospective research is needed to corroborate these findings in the general population.

Urinary Polycyclic Aromatic Hydrocarbon Metabolites and Human Semen Quality in China

Toxicological studies have demonstrated that polycyclic aromatic hydrocarbons (PAHs) exposure impairs male reproductive health. However, the epidemiological evidence is limited and discordant. Our goal was to investigate the relationship between PAH exposures and human semen quality. We analyzed 12 urinary metabolites of PAHs from 933 men who sought semen quality analysis in an infertility clinic in Wuhan, China. Associations with semen quality were assessed using a multivariable linear regression. Restricted cubic splines were used to explore the dose-response relationships between urinary metabolites of PAHs and semen quality. We observed inverse associations between urinary 1-hydroxynaphthalene (1-OHNa) and sperm count, sperm concentration, and percentage of normal morphology (all p for trends <0.05) as well as between urinary ∑OHNa (sum of 1-OHNa and 2-OHNa) and sperm concentration (p for trend =0.04). Additionally, we found inverse associations between urinary 9-hydroxyphenanthrene (9-OHPh) and semen volume and sperm straight-line velocity (both p for trends <0.05) as well as between urinary ∑OHPh (sum of 1-, 2-, 3-, 4-, and 9-OHPh) and sperm count (p for trend =0.04). These dose-response relationships were further confirmed in the curves of the restricted cubic splines. Our data suggest that exposure to naphthalene and phenanthrene is related to decreased semen quality. Our results contribute to the growing body of evidence regarding the widespread exposure to PAHs and the detriment to male reproductive function.

Urinary metabolites of polycyclic aromatic hydrocarbons, sperm DNA damage and spermatozoa apoptosis

Inconsistent results between polycyclic aromatic hydrocarbons (PAHs) exposure and adverse male reproductive health have been reported in humans. To assess whether PAH exposure is associated with declined sperm function. Ten monohydroxylated PAHs (OH-PAHs) metabolites were analyzed in repeated urine samples from an infertility clinic. We used multivariable linear models to estimate the associations of urinary OH-PAH metabolites with sperm DNA damage (n=405) and spermatozoa apoptosis (n=366). The shapes of dose-dependent associations of exposure measurements with outcomes were further evaluated by restricted cubic splines. Multiple comparisons were adjusted by false discovery rate (FDR). We found that urinary 9-hydroxyfluorene (9-OHFlu) was associated with increased tail length and comet length (p for trend=0.05 and 0.01, respectively), and that urinary 9-hydroxyphenanthrene (9-OHPh) was associated with decreased percentage of Annexin V-/PI- spermatozoa (p for trend=0.04). Also, suggestive associations of urinary 9-OHPh and ∑OHFlu with increased comet length, and urinary 9-OHFlu and 2-OHPh with decreased percentage of Annexin V-/PI- spermatozoa were observed (all p for trends <0.10). Further, these dose-dependent associations were confirmed in restricted cubic splines. Our results suggest that environmental exposure to fluorene and phenanthrene are associated with declined sperm function.

Predictors and correlations of phthalate metabolite concentrations in urine and seminal plasma among reproductive-aged men

Background: Certain phthalates are suspected to be endocrine disruptors that are adversely associated with male reproductive health. However, the predictors and correlations of phthalate metabolite concentrations in urine and seminal plasma among reproductive‐aged men have not been thoroughly studied. Objective: To investigate the predictors and correlations of phthalate metabolite concentrations in urine and seminal plasma among adult Chinese males. Method: We measured mono‐n‐butyl phthalate (MBP), monobenzyl phthalate (MBzP), monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono‐n‐octyl phthalate (MOP), mono(2‐ethylhexyl) phthalate (MEHP), mono(2‐ethyl‐5‐hydroxyhexyl) phthalate (MEHHP) and mono(2‐ethyl‐5‐oxohexyl) phthalate (MEOHP) concentrations in seminal plasma and repeated spot‐urine samples from 687 men who visited a reproductive center. Mixed‐effect models were used to examine the associations of sociodemographic, lifestyle and medical factors with urinary metabolite concentrations. Linear regression models were used to identify predictors of metabolite concentrations in seminal plasma and correlations between metabolite concentrations in spot urine samples and seminal plasma. Results: Measurements taken from spot urine samples poorly predicted same‐day seminal plasma concentrations (all R2<0.10). Inverse associations were observed between education level and urinary MBP and MEOHP and between household income and urinary MMP; receiving intravenous infusion therapy was associated with increased urinary MBP, MEHHP and MEOHP, use of facial cleanser/cream was associated with increased MEP, and smoking was associated with increased MEHP. The predictors of metabolite concentrations in seminal plasma differed from those in urine, except for the association of intravenous infusion therapy with MBP. BMI was associated with increased seminal plasma MBP, MEHP and MEOHP, smoking was associated with increased MEP, and contact with plastics was associated with increased MEOHP. Conclusions: Phthalate metabolite concentrations in adult men varied in accordance with sociodemographic variables, lifestyle factors and intravenous therapy. Measures of metabolite levels in urine may not directly reflect the exposure status of the male reproductive system. HIGHLIGHTSPhthalate metabolite levels in urine and seminal plasma were detected among 687 men.Measures taken from urine samples poorly predicted same‐day seminal plasma levels.Metabolite levels varied according to sociodemographic and lifestyle factors.Venous infusion was associated with higher levels of MBP and DEHP metabolites.

Repeated measures of urinary polycyclic aromatic hydrocarbon metabolites in relation to altered reproductive hormones: A cross-sectional study in China

BACKGROUND Polycyclic aromatic hydrocarbons (PAHs) are a group of ubiquitous environmental pollutants. In vivo and in vitro studies have demonstrated that PAHs can alter endocrine function, yet evidence from human studies is limited. OBJECTIVES The objective of this study was to investigate whether environmental exposure to PAHs was associated with altered reproductive hormone levels, using repeated measures of urinary OH-PAHs as biomarkers. METHODS We measured 10 monohydroxylated PAHs (OH-PAHs) in repeated urine samples from 371 men in an infertility clinic in Wuhan, China. Multivariable linear regression models were used to estimate the associations between average urinary OH-PAH levels and serum reproductive hormones, and restricted cubic spline models were further used to examine the shapes of dose-response relationships. RESULTS We observed dose-response associations of urinary 2-hydroxynaphthalene (2-OHNa) with decreased serum free testosterone (fT) and urinary 1-hydroxypyrene (1-OHP), 9-hydroxyphenanthrene (9-OHPh), and 9-hydroxyfluorene (9-OHFlu) with decreased serum estradiol (all P for trends <0.05). These associations were linear and significant when these four OH-PAHs were modeled as continuous variables in restricted cubic spline models. Furthermore, a U-shaped association was observed across urinary 4-OHPh levels, with lower levels of serum sex hormone-binding globulin (SHBG) at median concentrations compared with 5th and 95th percentile concentrations. CONCLUSION Environmental levels of PAH exposure in our study are associated with altered reproductive hormones. However, further research is needed to confirm our findings.

First-trimester blood concentrations of drinking water trihalomethanes and neonatal neurobehavioral development in a Chinese birth cohort

Toxicological evidence indicates that exposure to drinking water trihalomethanes (THMs) can impair neural development. However, no epidemiologic study to date has evaluated the relation of trihalomethanes exposure with neonatal neurobehavioral development. Here we aimed to evaluate if prenatal exposure to THMs during early pregnancy is associated with neonatal neurobehavioral development in 451 Chinese mother-child pairs. First trimester blood THMs [chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and bromoform (TBM)] were determined by solid phase micro-extraction gas chramatography. Neonatal neurobehavioral development was assessed using neonatal behavioral neurological assessment (NBNA) on the third day after birth. Multivariable linear regression models and restricted cubic spline models were constructed to evaluate the associations between blood THMs and neonatal neurological development scores. Blood concentrations of BDCM, whether modeled as continuous or categorical variables, were inversely associated with total NBNA score of newborns based on the multivariable linear regression. The association was further confirmed in the cubic spline model, and a linear dose-response relationship was observed. Stratified analysis showed that the inverse association between blood BDCM and total NBNA score was more evident in male infants than females. Our findings suggest that exposure to THMs during early pregnancy may be associated with impaired neonatal neurobehavioral development.

Concentrations of vanadium in urine and seminal plasma in relation to semen quality parameters, spermatozoa DNA damage and serum hormone levels

Widespread human exposure to vanadium has been well documented. Vanadium exposure was reported to induce male reproductive toxicity in toxicological studies, yet human epidemiologic studies are lacking. Here we determined the associations between environmental exposure to vanadium and semen quality, spermatozoa DNA damage and serum reproductive hormones. Concentrations of vanadium in seminal plasma and repeated urine samples were determined among 764 men recruited from a reproductive medicine centre. Associations of vanadium concentrations with semen quality parameters (n = 764), DNA integrity measures (n = 404) and serum reproductive hormones (n = 381) were assessed by logistic or linear regression models with adjustment for potential confounders. Significant positive dose-response relationships were observed between vanadium concentrations in seminal plasma and tail length and serum estradiol, as well as odds ratios for a below-reference-value sperm concentration; whereas inverse relationships between seminal plasma vanadium with total testosterone (T) and free T (all p values for trends <0.05) were observed. These relationships were maintained after adjusting for seminal plasma concentrations of other elements (i.e., arsenic, cadmium, copper, selenium, or tin). No significant associations was revealed between urinary vanadium concentrations and semen quality, spermatozoa DNA integrity and reproductive hormones. Our findings suggested that elevated vanadium exposure may be adversely associated with male reproductive health, and that seminal plasma vanadium may be a more direct exposure biomarker for the male reproductive system than urinary vanadium.

Thyroid function, phthalate exposure and semen quality: Exploring associations and mediation effects in reproductive-aged men

BACKGROUND A normal thyroid physiology is crucial for the maintenance of male reproductive health. Changes in thyroid hormones may represent an intermediate biological mechanism linking phthalate exposure and potential adverse health effects on male reproduction. OBJECTIVE To investigate the mediating role of thyroid function on the association between phthalate exposure and semen quality. METHOD Serum thyroid hormones, semen quality and repeated measures of urinary phthalate metabolites were determined among 509 reproductive-aged men in Wuhan, China. Cross-sectional associations between urinary phthalate metabolites, serum thyroid hormones and semen quality were explored using multivariable linear regressions. A mediation analysis was conducted to explore the role of thyroid function on the association of phthalate exposure with semen quality. RESULTS Significant dose-dependent relationships were found across quartiles of monoethyl phthalate (MEP) with decreasing serum free thyroxine (FT4), which, in turn, was negatively associated with percentage of normal morphology (p for trend = 0.04). Also, we found that the proportions of di-(2-ethylhexyl)-phthalate metabolites excreted as mono-(2-ethylhexyl) phthalate (%MEHP) were negatively associated with serum thyroid-stimulating hormone (TSH) (all p for trends <0.05), which, in turn, was positively associated with progressive and total sperm motility (p for trends = 0.04 and 0.03, respectively). The mediation analysis indicated that higher urinary MEP was significantly associated with a decreasing percentage of normal morphology after controlling for thyroid hormones, and 17% of the association was mediated by serum FT4. CONCLUSIONS Higher urinary MEP and %MEHP were associated with decreasing serum thyroid hormones, which in turn were associated with altered semen quality. Mediation analysis indicated that serum FT4 was a possible mediator of the association between urinary MEP and proportion of normal sperm morphology.

Prenatal phthalate exposure, birth outcomes and DNA methylation of Alu and LINE-1 repetitive elements: A pilot study in China

BACKGROUND Epigenetic mechanisms, such as altered DNA methylation, may participate in the relationship between prenatal phthalate exposure and adverse birth outcomes. OBJECTIVE To explore the mediation effect of DNA methylation in the associations of phthalate exposure before delivery with birth outcomes in a Chinese cohort. METHODS Eight phthalate metabolites in maternal urine before delivery and DNA methylation of Alu and long interspersed nucleotide elements (LINE-1) in cord blood were determined among 106 mother-infant pairs. General additive models were used to assess the associations of maternal urinary phthalate metabolites with birth outcomes and DNA methylation; the mediating role of DNA methylation in cord blood was evaluated by mediation analysis. RESULTS We found sex-specific associations between prenatal phthalate exposure and birth outcomes and DNA methylation of cord blood. For example, the molar sum of di-2-(ethylhexyl) phthalate (∑DEHPm) metabolites in maternal urine was positively associated with gestational age among male newborns only (P < 0.05); maternal urinary monobenzyl phthalate (MBzP) was negatively associated with Alu methylation among female newborns only (P < 0.05). Mediation analysis did not find that methylation of Alu and LINE-1 to be a direct mediator in the relationships between maternal urinary phthalate metabolites before delivery and birth outcomes. CONCLUSION Prenatal exposure to certain phthalates was associated with altered birth outcomes and decreased repetitive element methylation of newborns. However, the altered birth outcomes exerted by prenatal phthalate exposure does not seem to be directly mediated through repetitive element methylation in cord blood.