Phthalates Induce Androgenic Effects at Exposure Levels That Can Be Environmentally Relevant in Humans

Abstract

Although anti-androgenic activity of various lipophilic chain phthalate acid esters (PAEs) has been reported in high-dose animal studies, their male reproductive risk remains a matter of debate because of conflicting epidemiological observations. Recently, we showed that PAEs acted as a preventative factor in male infertility, which implies these chemicals are androgenic in human steroidogenesis. To verify the androgenic observation, a reproductive age healthy male cohort (n = 84) was recruited by following a cross-sectional study design, in which infertility or clinical selection-introduced bias was avoided. Urine was used for both PAE exposure monitoring and androgen measurements, and sampling uncertainty was greatly reduced. Eight selected metabolites (i.e., MMP, MEP, MBP, MEHP, MBzP, MEHHP, MECPP, and MEOHP) and two androgens, i.e., androstenedione (ASD) and testosterone, were measured by using HPLC–MS/MS. Except for MBzP, the selected phthalates can be detected in all samples at concentrations (median [5th–95th percentile]) of 36.4 [2.0–261.0], 36.7 [5.6–318.5], 75.3 [13.1–301.0], 3.2 [1.1–10.2], 3.8 [0.6–11.9], 13.6 [1.6–51.1], and 7.4 [0.9–31.8] ng/mL for MMP, MEP, MBP, MEHP, MEOHP, MECPP, and MEHHP, respectively. Urinary PAE metabolites generally correlated with ASD and testosterone in positive ways; the trends are most significant for MMP, MEP, MBP, and ∑DEHP versus ASD and for ∑DEHP versus testosterone. This study reveals that the phenotypic effect of our participants’ exposure to PAEs at the typical environmental relevant exposure level is androgenic, which counters the notion of the well-accepted anti-androgenic effect.