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

Wei Hsiang Chang, Sih Syuan Li, Meng Hsing Wu, Hsien An Pan, Ching Chang Lee

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

STUDY QUESTION Do phthalates create a male reproductive hormone imbalance by down-regulating the secretion of testosterone and insulin-like factor 3 (INSL3)? SUMMARY ANSWER Our study suggests that exposure to phthalates is related to a reduction in the secretion of testosterone and INSL3 in adult males. WHAT IS KNOWN ALREADY 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. STUDY DESIGN, SIZE, DURATION 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. PARTICIPANTS/MATERIALS, SETTING, METHODS 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. MAIN RESULTS AND THE ROLE OF CHANCE 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 (P trend = 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). LIMITATIONS, REASONS FOR CAUTION 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. WIDER IMPLICATIONS OF THE FINDINGS 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. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grants NSC 100-2314-B-006-054 and NSC 101-2314-B-006-052-MY2 from the Taiwan Ministry of Science and Technology. The authors have no conflicts of interest to disclose.

Original languageEnglish
Pages (from-to)2658-2670
Number of pages13
JournalHuman Reproduction
Volume30
Issue number11
DOIs
Publication statusPublished - 2015 May 26

Fingerprint

Testosterone
Insulin
Dibutyl Phthalate
Serum
Leydig Cells
Androgens
phthalic acid
Taiwan
Infertility
Linear Models
mono-(2-ethylhexyl)phthalate
Prenatal Education
Hormones
Plasticizers
Conflict of Interest
Sex Hormone-Binding Globulin
Organized Financing
Population
Radioimmunoassay
Case-Control Studies

All Science Journal Classification (ASJC) codes

  • Reproductive Medicine
  • Obstetrics and Gynaecology

Cite this

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title = "Phthalates might interfere with testicular function by reducing testosterone and insulin-like factor 3 levels",
abstract = "STUDY QUESTION Do phthalates create a male reproductive hormone imbalance by down-regulating the secretion of testosterone and insulin-like factor 3 (INSL3)? SUMMARY ANSWER Our study suggests that exposure to phthalates is related to a reduction in the secretion of testosterone and INSL3 in adult males. WHAT IS KNOWN ALREADY 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. STUDY DESIGN, SIZE, DURATION 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. PARTICIPANTS/MATERIALS, SETTING, METHODS 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. MAIN RESULTS AND THE ROLE OF CHANCE 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 (P trend = 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). LIMITATIONS, REASONS FOR CAUTION 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. WIDER IMPLICATIONS OF THE FINDINGS 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. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grants NSC 100-2314-B-006-054 and NSC 101-2314-B-006-052-MY2 from the Taiwan Ministry of Science and Technology. The authors have no conflicts of interest to disclose.",
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Phthalates might interfere with testicular function by reducing testosterone and insulin-like factor 3 levels. / Chang, Wei Hsiang; Li, Sih Syuan; Wu, Meng Hsing; Pan, Hsien An; Lee, Ching Chang.

In: Human Reproduction, Vol. 30, No. 11, 26.05.2015, p. 2658-2670.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phthalates might interfere with testicular function by reducing testosterone and insulin-like factor 3 levels

AU - Chang, Wei Hsiang

AU - Li, Sih Syuan

AU - Wu, Meng Hsing

AU - Pan, Hsien An

AU - Lee, Ching Chang

PY - 2015/5/26

Y1 - 2015/5/26

N2 - STUDY QUESTION Do phthalates create a male reproductive hormone imbalance by down-regulating the secretion of testosterone and insulin-like factor 3 (INSL3)? SUMMARY ANSWER Our study suggests that exposure to phthalates is related to a reduction in the secretion of testosterone and INSL3 in adult males. WHAT IS KNOWN ALREADY 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. STUDY DESIGN, SIZE, DURATION 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. PARTICIPANTS/MATERIALS, SETTING, METHODS 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. MAIN RESULTS AND THE ROLE OF CHANCE 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 (P trend = 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). LIMITATIONS, REASONS FOR CAUTION 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. WIDER IMPLICATIONS OF THE FINDINGS 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. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grants NSC 100-2314-B-006-054 and NSC 101-2314-B-006-052-MY2 from the Taiwan Ministry of Science and Technology. The authors have no conflicts of interest to disclose.

AB - STUDY QUESTION Do phthalates create a male reproductive hormone imbalance by down-regulating the secretion of testosterone and insulin-like factor 3 (INSL3)? SUMMARY ANSWER Our study suggests that exposure to phthalates is related to a reduction in the secretion of testosterone and INSL3 in adult males. WHAT IS KNOWN ALREADY 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. STUDY DESIGN, SIZE, DURATION 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. PARTICIPANTS/MATERIALS, SETTING, METHODS 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. MAIN RESULTS AND THE ROLE OF CHANCE 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 (P trend = 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). LIMITATIONS, REASONS FOR CAUTION 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. WIDER IMPLICATIONS OF THE FINDINGS 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. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grants NSC 100-2314-B-006-054 and NSC 101-2314-B-006-052-MY2 from the Taiwan Ministry of Science and Technology. The authors have no conflicts of interest to disclose.

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