The association of serum phthalate metabolites with biomarkers of ovarian reserve in women of childbearing age

Abstract

Phthalates (PAEs) are widely used plasticizers drawing increasing concern due to reproductive toxicity. However, studies on serum PAEs metabolites (mPAEs) and their associations with human ovarian function remain very scarce. In this study, from April 2019 to August 2020, a total of 297 women of childbearing age were recruited in Tianjin, China. Eleven mPAEs were analyzed in serum samples and eight mPAEs were detected at frequencies > 65% with median concentrations of 0.43–15.3 ng/mL. In multinomial logistic analysis, an increase in serum mono (2-isobutyl) phthalate (miBP) was associated with decline in antral follicle count (AFC) (OR=1.26, 95% CI: 0.99, 1.61) and 5-mono-(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP) was significantly associated with AFC increase (OR=1.43, 95% CI: 1.06, 1.92), which were aligned with the associations found between mPAEs and AMH through generalized linear regression. In multiple linear regression models, per 10% increase in serum mono (2-ethylhexyl) phthalate (mEHP), mono (2-ethyl-5-oxohexyl) phthalate (mEOHP) (oxo-mEHP), and principal component 1 featured for high concentrations of mono-n-butyl phthalate (mBP), miBP and mEHP were associated with 0.15 (95% CI: −0.29, −0.02), 0.01 (95% CI: −0.01, 0.00) and 0.01 (95% CI: −0.02, 0.00) ln-unit decrease in estradiol (E2) levels, respectively, while mono-[(2-carboxymethyl) hexyl] phthalate (mCMHP) (carboxymethyl-mEHP) was positively associated with 0.05 ln-unit increase of E2 (95% CI: 0.02, 0.08). The observed negative associations between mPAEs and the Anti-Müllerian hormone (AMH) also aligned with the change in AFC. Generalized linear regression also revealed nonlinear associations between mono-ethyl phthalate (mEP), mCMHP and follicle-stimulating hormone (FSH). Overall, serum mEHP and its metabolites were negatively associated with E2. miBP was negatively associated with AFC. The nonlinear associations between mPAEs and FSH, and AMH need further study.