The relationships between urinary phthalate metabolites, reproductive hormones and semen parameters in men attending in vitro fertilization clinic

Abstract

Evidence from previous studies has shown that phthalates may play a role in male reproductive function; however, results are still inconclusive, and the mechanism remains unclear. In this study, we first assessed whether exposure to phthalates is associated with altered reproductive hormones and semen parameters in 599 men attending an in vitro fertilization clinic. Secondly, we evaluated whether reproductive hormones could play a mediating role in the association between phthalates and sperm parameters. Eight phthalate metabolites were measured in two different spot urine samples: mono‑n‑butyl phthalate, mono-isobutyl phthalate (MiBP), monoethyl phthalate (MEP), monobenzyl phthalate, and four oxidative metabolites of di‑(2‑ethylhexyl) phthalate (DEHP) [i.e., mono‑(2‑ethylhexyl) phthalate (MEHP), mono‑(2‑ethyl‑5‑hydroxyhexyl) phthalate (MEHHP), mono‑(2‑ethyl‑5‑oxohexyl) phthalate (MEOHP), and mono‑(2‑ethyl‑5‑carboxypentyl) phthalate (MECPP)]. Semen parameters (concentration, volume, motility, and morphology) and reproductive hormones, i.e., follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone, estradiol (E₂), testosterone (TEST) and prolactin (PROL) were also determined and considered the main study outcomes. Separate multivariate linear regression was used to assess associations between levels of each urinary phthalate metabolite, molar sum of DEHP metabolites (∑DEHP), percentage of MEHP to ∑DEHP (%MEHP), and each outcome (natural log-transformed). Inverse associations were observed between TEST and MiBP (β = -0.099), FSH and MEHHP (β = -0.087), and PROL and MEOHP (β = -0.102), while a positive relationship was seen between E₂ and MEP (β = 0.098). %MEHP was associated positively with FSH (β = 0.118) and LH (β = 0.099), but negatively with TEST/LH (β = -0.086) and TEST/E₂ (β = -0.109). Sperm concentration was associated positively with MECPP (β = 0.131), MEHHP (β = 0.117), MEOHP (β = 0.107) and ∑DEHP (β = 0.111), but negatively with %MEHP (β = -0.135). All p-values were <0.05. Sobel's test indicated that FSH mediated significantly up to 60% of the positive relationship between sperm concentration and MEHHP, while FSH and LH mediated respectively 15 and 12% of the inverse association between sperm concentration and %MEHP. Further research on this topic is warranted.

Keywords: Endocrine-disruptor; Male infertility; Phthalates; Reproductive hormones; Semen parameters.