Associations of bisphenol and phthalate exposure and anti-Müllerian hormone levels in women of reproductive age

Abstract

Background: In women, exposure to endocrine disrupting chemicals might accelerate the depletion of the ovarian reserve and might be associated with accelerative reproductive aging and fertility. We examined the longitudinal associations of exposure to bisphenols and phthalates with anti-Müllerian hormone concentrations.

Methods: Pregnant women of 18 years or older that resided in Rotterdam between 2002 and 2006 were eligible for participation in this longitudinal prospective cohort study. We measured urinary bisphenol and phthalate concentration at three time-points in pregnancy among 1405 women, of whom 1322 women had serum Anti-Müllerian Hormone (AMH) measurements 6 and/or 9 years postpartum. We performed linear regression models to assess the association of urinary bisphenol and phthalate metabolites with AMH after 6 and 9 years, and linear mixed-effect model to assess the association with AMH over time. Models were adjusted for sociodemographic and lifestyle factors.

Findings: In our multivariable linear regression models we observed associations of higher urinary pregnancy-averaged mono-isobutyl phthalate (mIBP), mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP), and monobenzyl phthalate (mBzBP) with lower serum AMH after both 6 and 9 years. However, these associations did not remain after adjustment for multiple testing. No significant associations of bisphenol A with AMH were present in our study sample. In our linear mixed-effects models, higher mIBP, mono-(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mEOHP, and mBzBP were associated with lower overall AMH levels (differences -0.07 (95% CI -0.13, -0.02), -0.09 (-0.15, -0.02), -0.08 (95% CI -0.14, -0.02), and -0.08 (-0.13, -0.03) μg/L per doubling in mIBP, mEHHP, mEOHP, and mBzBP respectively) (all False Discovery Rate adjusted p-values < 0.05).

Interpretation: We identify decreases in indices of ovarian reserve in relationship to prenatal phthalate exposures. Studies are needed replicating our results among large multi-ethnic non-pregnant populations and assessing transgenerational effects of exposure on ovarian reserve.

Funding: This study was supported by the Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organisation for Health Research and Development, the European Research Council, the Dutch Heart Foundation, the Dutch Diabetes Foundation, the European Union's Horizon 2020 Research and Innovation Program, the National Institutes of Health, Ansh Labs Webster, and the Royal Netherlands Academy of Arts and Sciences.

Keywords: Bisphenols; Ovarian reserve; Phthalates; anti-Müllerian hormone.

Fig. 1

Flowchart of participants included in the study.

Fig. 2

Associations of urinary bisphenol and phthalate concentrations with serum anti-Müllerian hormone levels in A) 6 years and B) 9 years postpartum, and C) on average, obtained from multivariable linear regression models. Models reflect the change (95% confidence interval (CI)) in maternal serum Anti-Müllerian hormone (AMH) levels (μg/L) 6 years and 9 years postpartum, and on average per doubling in maternal urinary pregnancy-averaged bisphenol or phthalate metabolite or metabolite group (nmol/L). Models are adjusted for maternal urinary creatinine concentrations, maternal age at exposure and outcome measurement, ethnicity, educational level, parity, smoking, alcohol use and body-mass index at exposure measurement. BPA bisphenol A, BPS bisphenol S, BPF bisphenol F, PA phthalic acid, mMP monomethylphthalate, mEP monoethylphthalate, mIBP mono-isobutylphthalate, mBP mono-n-butylphthalate, mECPP mono-(2-ethyl-5-carboxypentyl)phthalate, mEHHP mono-(2-ethyl-5-hydroxyhexyl)phthalate, mEOHP mono-(2-ethyl-5-oxohexyl)phthalate, mCMHP mono[(2-carboxymethyl)-hexyl]phthalate, mBzP monobenzylphthalate, mHxP mono-hexylphthalate, mHpP mono-2-heptylphthalate, BP total bisphenol, LMW low molecular weight phthalate, DEHP di-2-ethylhexyl phthalate, DNOP di-n-octylphthalate, HMW high molecular weight phthalate. Corresponding data are presented in Supplementary Table S5.

Fig. 3

Associations of urinary bisphenol and phthalate concentrations with serum anti-Müllerian hormone levels, obtained from linear mixed-effects models, adjusted model. Models reflect the change (95% confidence interval (CI)) in maternal serum Anti-Müllerian (AMH) hormone levels (ug/L) per doubling in maternal urinary pregnancy-averaged bisphenol or phthalate metabolite or metabolite group (nmol/L). Effect estimates were obtained from linear mixed-effects models and adjusted for maternal urinary creatinine concentrations, maternal age at baseline, ethnicity, educational level, parity, smoking, alcohol use and body-mass index at exposure measurement. BPA bisphenol A, BPS bisphenol S, BPF bisphenol F, PA phthalic acid, mMP monomethylphthalate, mEP monoethylphthalate, mIBP mono-isobutylphthalate, mBP mono-n-butylphthalate, mECPP mono-(2-ethyl-5-carboxypentyl)phthalate, mEHHP mono-(2-ethyl-5-hydroxyhexyl)phthalate, mEOHP mono-(2-ethyl-5-oxohexyl)phthalate, mCMHP mono[(2-carboxymethyl)-hexyl]phthalate, mBzP monobenzylphthalate, mHxP mono-hexylphthalate, mHpP mono-2-heptylphthalate, BP total bisphenol, LMW low molecular weight phthalate, DEHP di-2-ethylhexyl phthalate, DNOP di-n-octylphthalate, HMW high molecular weight phthalate. Corresponding data are shown in Supplementary Table S9.