Phthalates might interfere with testicular function by reducing testosterone and insulin-like factor 3 levels.

Do phthalates create a male reproductive hormone imbalance by down-regulating the secretion of testosterone and insulin-like factor 3 (INSL3)? Our study suggests that exposure to phthalates is related to a reduction in the secretion of testosterone and INSL3 in adult males. There is evidence that exposure to phthalates, an abundant group of industrial plasticizers, negatively affects testosterone biosynthesis, but little is known about the mechanism in men. The hypothesis that exposure to phthalates reduces the levels of testosterone and INSL3, a marker of Leydig cell function, is underexplored. This case-control study of 176 men ran from 2010 to 2012. Infertile men were recruited through infertility clinics in Taiwan, fertile men were recruited from childbirth preparation classes and all were categorized based on the World Health Organization definition of infertility and by the diagnoses of obstetricians. Urinary concentrations of 11 phthalate metabolites were measured, along with serum levels of FSH, LH, total testosterone (TT), estradiol, sex hormone-binding globulin and Inhibin B. Androgen status indices including free testosterone (fT) and the free androgen index (FAI) were calculated. The circulating INSL3 level was evaluated using a radioimmunoassay. Non-parametric analyses, trend tests and linear regression models were used. Urinary mono-n-butyl phthalate (MnBP), mono-(2-ethylhexyl) phthalate (MEHP) and mono-2-ethyl-5-carboxypentyl phthalate were significantly higher in infertile than in fertile men. Serum Inhibin B, the Inhibin B : FSH ratio, the TT : LH ratio and INSL3 were significantly lower in infertile men. In multiple regression models controlled for potential confounders, there is an inverse association between urinary levels of mono-methyl phthalate (MMP), mono-iso-butyl phthalate (MiBP), MEHP, MEHP% and serum TT (P = 0.001, 0.007, 0.042 and 0.012, respectively). The inverse associations were also found between urinary levels of MiBP, monobenzyl phthalate (MBzP), MEHP, MEHP% and serum fT (P = 0.028, 0.017, 0.045 and 0.027, respectively); between urinary levels of MMP, MEHP, MEHP% and the TT : LH ratio (P = 0.004, 0.029 and 0.039, respectively); between urinary levels of MMP, MiBP, MnBP, MBzP, MEHP and the FAI (P = 0.002, 0.008, 0.037, 0.028, 0.042 and 0.016, respectively). Urinary MBzP and MEHP% were negatively associated with a decrease in serum INSL3 (P = 0.049 and <0.001). We also observed a strong inverse relationship between MEHP% quartiles and serum TT, fT, the TT : LH ratio and INSL3 (Ptrend = 0.003, 0.080, 0.002 and 0.012, respectively). Serum INSL3, TT, fT and the TT : LH ratio were lower for men in the highest MEHP% quartile than in the reference group (P = 0.007, 0.002, 0.090 and 0.001, respectively). A potential limitation is using a single urine and blood sample to predict urinary phthalate metabolites and reproductive hormone status over long periods. However, there is evidence that a single measure provides a reliable result in population studies. Non-occupational exposure to phthalates, including di-2-ethylhexyl phthalate, might lead to adverse effects on testicular/Leydig cell function and be of concern owing to the ubiquitous multisource exposure to phthalates among the general population. Although our findings are in agreement with recent experimental data, more studies are required to draw firm conclusions on the relation of INSL3 to phthalate exposure or testicular/Leydig cell function.

Chang WH ，Li SS ，Wu MH ，Pan HA ，Lee CC ... -  《-》

Semen quality and insulin-like factor 3: Associations with urinary and seminal levels of phthalate metabolites in adult males.

Certain phthalates have adverse effects on male reproductive functions in animals, and potentially affect human testicular function and spermatogenesis, but little is known about the active mechanisms. We measured the urinary and seminal phthalate metabolites and explored their associations on insulin-like factor 3 (INSL3) and semen quality. Urine, blood, and semen samples were collected from the male partners of subfertile (n = 253) and fertile (n = 37) couples in a reproductive center in southern Taiwan. INSL3, reproductive hormones, semen-quality, and 11 phthalate metabolites in urine and semen were measured. There were significant correlations in the distribution pattern of metabolites, such as the relative contribution of low or high molecular weight phthalate metabolites. The significantly monotonic trends in semen volume, sperm concentration and motility were associated with increasing quartiles of INSL3 (all p-trend < 0.001). In adjusted regression models, increases in urinary phthalate metabolites levels were adversely associated with sperm concentration (monobenzyl phthalate [MBzP], mono-2-ethylhexyl phthalate [MEHP] and MEHP%), motility (MBzP and MEHP) and INSL3 (MBzP, MEHP and MEHP%) (all p < 0.01). Higher seminal phthalate metabolite levels were associated with decreases in sperm concentration (MEHP and mono-2-ethyl-5-hydroxyhexyl phthalate), motility (mono-ethyl phthalate [MEP] and di-(2-ethylhexyl) phthalate [DEHP] metabolites), normal morphology (MEP), and INSL3 (monomethyl phthalate and MEP) (all p < 0.05). Our data suggest that INSL3 secretion, reproductive hormone balance, and sperm production and quality might be simultaneously adversely affected for individuals excreting increasing levels of phthalates metabolites (especially di-ethyl phthalate, butylbenzyl phthalate, and DEHP) in urine and semen samples.

Chang WH ，Wu MH ，Pan HA ，Guo PL ，Lee CC ... -  《-》

Association between phthalate metabolites and biomarkers of reproductive function in 1066 Chinese men of reproductive age.

Phthalates are suspected endocrine disrupting chemicals that impair male reproductive function in animal and epidemiological studies. We investigated associations between urinary phthalate metabolites and acrosin activity, along with that between insulin like-factor 3 (INSL3), a Leydig cell function marker, in Chinese adult men and assessed the association between the metabolites and male reproductive function. Serum levels of INSL3 and other hormones, semen parameters, and urinary concentrations of 14 phthalate metabolites in 1066 men were measured. The unadjusted concentrations of phthalates were included as independent variables and urinary creatinine as a separate covariate. INSL3 was negatively associated with mono-2-ethylhexyl phthalate (MEHP) and %MEHP [percentage of MEHP to all di(2-ethylhexyl) phthalate (DEHP) metabolites]. Acrosin activity was negatively associated with mono-n-butyl phthalate (MBP), mono-isobutyl phthalate (MiBP), MEHP and %MEHP. MBP and MiBP were also negatively associated with total testosterone (T), free androgen index (FAI), free testosterone (FT), luteinizing hormone (LH) and sperm morphology and positively associated with DNA fragmentation index (DFI). A negative association between %MEHP and sperm motility was observed. Several other metabolites were also associated with reproductive function. This is the first report on the inverse associations of phthalate metabolites with acrosin activity and INSL3. Phthalates may cause multiple adverse results on reproductive function at environmental levels.

Pan Y ，Jing J ，Dong F ，Yao Q ，Zhang W ，Zhang H ，Yao B ，Dai J ... -  《-》

Biomonitoring of phthalate metabolites in the Canadian population through the Canadian Health Measures Survey (2007-2009).

Human exposure to phthalates occurs through multiple sources and pathways. In the Canadian Health Measures Survey 2007-2009, 11 phthalate metabolites, namely, MMP, MEP, MnBP, MBzP, MCHP, MCPP, MEHP, MEOHP, MEHHP, MnOP, and MiNP were measured in urine samples of 6-49 year old survey respondents (n=3236). The phthalate metabolites biomonitoring data from this nationally-representative Canadian survey are presented here. The metabolites MEP, MnBP, MBzP, MCPP, MEHP, MEOHP and MEHHP were detected in >90% of Canadians while MMP, MCHP, MnOP and MiNP were detected in <20% of the Canadian population. Step-wise regression analyses were carried out to identify important predictors of volumetric concentrations (μg/L) of the metabolites in the general population. Individual multiple regression models with covariates age, sex, creatinine, fasting status, and the interaction terms age×creatinine, age×sex and fasting status×creatinine were constructed for MEP, MnBP, MBzP, MCPP, MEHP, MEOHP and MEHHP. The least square geometric mean (LSGM) estimates for volumetric concentration (μg/L) of the metabolites derived from respective regression models were used to assess the patterns in the metabolite concentrations among population sub-groups. The results indicate that children had significantly higher urinary concentrations of MnBP, MBzP, MEHP, MEHHP, MEOHP and MCPP than adolescents and adults. Moreover, MEP, MBzP, MnBP and MEOHP concentrations in females were significantly higher than in males. We observed that fasting status significantly affects the concentrations of MEHP, MEHHP, MEOHP, and MCPP metabolites analyzed in this study. Moreover, our results indicate that the sampling time could affect the DEHP metabolite concentrations in the general Canadian population.

Saravanabhavan G ，Guay M ，Langlois É ，Giroux S ，Murray J ，Haines D ... -  《-》

Trends of the internal phthalate exposure of young adults in Germany--follow-up of a retrospective human biomonitoring study.

The exposure of the general population to phthalates is of increasing public health concern. Variations in the internal exposure of the population are likely, because the amounts, distribution and application characters of the phthalate use change over time. Estimating the chronological sequences of the phthalate exposure, we performed a retrospective human biomonitoring study by investigating the metabolites of the five most prominent phthalates in urine. Therefore, 24h-urine samples from the German Environmental Specimen Bank (ESB) collected from 240 subjects (predominantly students, age range 19-29 years, 120 females, 120 males) in the years 2002, 2004, 2006 and 2008 (60 individuals each), were analysed for the concentrations of mono-n-butyl phthalate (MnBP) as metabolite of di-n-butyl phthalate (DnBP), mono-iso-butyl phthalate (MiBP) as metabolite of di-iso-butyl phthalate (DiBP), mono-benzyl phthalate (MBzP) as metabolite of butylbenzyl phthalate (BBzP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (5oxo-MEHP), mono-(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP) and mono-(2-carboxymethyl hexyl) phthalate (2cx-MMHxP) as metabolites of di(2-ethylhexyl) phthalate (DEHP), monohydroxylated (OH-MiNP), monooxidated (oxo-MiNP) and monocarboxylated (cx-MiNP) mono-iso-nonylphthalates as metabolites of di-iso-nonyl phthalates (DiNP). Based on the urinary metabolite excretion, together with results of a previous study, which covered the years 1988-2003, we investigated the chronological sequences of the phthalate exposure over two decades. In more than 98% of the urine samples metabolites of all five phthalates were detectable indicating a ubiquitous exposure of people living in Germany to all five phthalates throughout the period investigated. The medians in samples from the different years investigated are 65.4 (2002), 38.5 (2004), 29.3 (2006) and 19.6 μg/l (2008) for MnBP, 31.4 (2002), 25.4 (2004), 31.8 (2006) and 25.5 μg/l (2008) for MiBP, 7.8 (2002), 6.3 (2004), 3.6 (2006) and 3.8 μg/l (2008) for MBzP, 7.0 (2002), 5.6 (2004), 4.1 (2006) and 3.3 μg/l (2008) for MEHP, 19.6 (2002), 16.2 (2004), 13.2 (2006) and 9.6 μg/l (2008) for 5OH-MEHP, 13.9 (2002), 11.8 (2004), 8.3 (2006) and 6.4 μg/l (2008) for 5oxo-MEHP, 18.7 (2002), 16.5 (2004), 13.8 (2006) and 10.2 μg/l (2008) for 5cx-MEPP, 7.2 (2002), 6.5 (2004), 5.1 (2006) and 4.6 μg/l (2008) for 2cx-MMHxP, 3.3 (2002), 2.8 (2004), 3.5 (2006) and 3.6 μg/l (2008) for OH-MiNP, 2.1 (2002), 2.1 (2004), 2.2 (2006) and 2.3 μg/l (2008) for oxo-MiNP and 4.1 (2002), 3.2 (2004), 4.1 (2006) and 3.6 μg/l (2008) for cx-MiNP. The investigation of the time series 1988-2008 indicates a decrease of the internal exposure to DnBP by the factor of 7-8 and to DEHP and BzBP by the factor of 2-3. In contrast, an increase of the internal exposure by the factor of 4 was observed for DiNP over the study period. The exposure to DiBP was found to be stable. In summary, we found decreases of the internal human exposure for legally restricted phthalates whereas the exposure to their substitutes increased. Future investigations should verify these trends. This is of increasing importance since the European Commission decided to require ban or authorization from 1.1.2015 for DEHP, DnBP, DiBP and BzBP according to REACh Annex XIV.

Göen T ，Dobler L ，Koschorreck J ，Müller J ，Wiesmüller GA ，Drexler H ，Kolossa-Gehring M ... -  《-》