title: Phthalates might interfere with testicular function by reducing testosterone and insulin-like factor 3 levels.
abstract: OBJECTIVE
  Do phthalates create a male reproductive hormone imbalance by down-regulating the secretion of testosterone and insulin-like factor 3 (INSL3)?
  
  
  CONCLUSIONS
  Our study suggests that exposure to phthalates is related to a reduction in the secretion of testosterone and INSL3 in adult males.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 70403, Taiwan.
authors.forename: Wei-Hsiang
authors.initials: WH
authors.lastname: Chang
authors.affiliation: Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 70403, Taiwan.
authors.forename: Sih-Syuan
authors.initials: SS
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, Hospital of National Cheng Kung University, 138 Sheng-Li Road, Tainan 70403, Taiwan.
authors.forename: Meng-Hsing
authors.initials: MH
authors.lastname: Wu
authors.affiliation: An-An Women and Children Clinic, 286 Kaiyuan Road, Tainan 70403, Taiwan.
authors.forename: Hsien-An
authors.initials: HA
authors.lastname: Pan
authors.affiliation: Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 70403, Taiwan Research Center of Environmental Trace Toxic Substance, National Cheng Kung University, 138 Sheng-Li Road, Tainan 70403, Taiwan cclee@mail.ncku.edu.tw.
authors.forename: Ching-Chang
authors.initials: CC
authors.lastname: Lee
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D006801:Humans; D007248:Infertility, Male / Q000097:blood / Q000453:epidemiology / Q000652:urine; D007328:Insulin / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010795:Phthalic Acids / Q000652:urine*; D011506:Proteins; D013624:Taiwan; D013739:Testosterone / Q000097:blood*
chemical_list: D007328:Insulin; C084797:Leydig insulin-like protein; D010795:Phthalic Acids; D011506:Proteins; D013739:Testosterone; C032279:phthalic acid
keywords: insulin-like factor 3; leydig cell; reproductive hormone; testicular function; urinary phthalate metabolites