Environmental Chemicals as Modifiers of the Association between Age and Ovarian Reserve

To evaluate whether the well-established age-related reduction in antral follicle counts (AFC) is greater among women with higher concentrations of endocrine-disrupting chemicals. Prospective cohort study using the doubly robust (DR) learner, a flexible machine learning method that models the relationship between an exposure and outcome of interest and identifies potential modifiers of this relation. Seven hundred seventy-five women aged 21-46 years enrolled in The Environment and Reproductive Health (EARTH) Study at the Massachusetts General Hospital Fertility Center, Boston, USA, between 2004 and 2019. Age at AFC assessment calculated as the date of antral follicle scan minus the patient’s birthdate, categorized into <35 years or ≥35 years. We assessed urinary concentrations of 16 endocrine-disrupting chemicals, including 11 urinary phthalate metabolites, 3 urinary parabens, urinary bisphenol A, and hair mercury, as potential modifiers of the age- AFC association. AFC assessed by transvaginal ultrasonography. In this cohort of 775 women, 43% were less than 35 years of age. Women greater than or equal to aged 35 years had lower AFC (mean [SD]: 11.63 [6.24] vs. 16.89 [8.64]) Three endocrine-disrupting chemicals significantly modified the age-AFC association. Women with higher urinary mono-isobutyl phthalate (MiBP) and monocarboxyisooctyl phthalate (MCOP) concentrations experienced stronger negative associations between age and AFC. Threshold analyses revealed that the age-AFC association strengthened, declining at a faster rate when MiBP, MCOP, or MEHP concentrations were higher. Women with higher hair Hg concentrations experienced weaker negative associations between age and AFC. The remaining 13 endocrine- disrupting chemicals did not modify the age-AFC relationship. Select phthalate metabolites, specifically MiBP, MCOP, and MEHP, were associated with a modified age-related decline in ovarian reserve in a curvilinear dose- dependent manner. These findings add to the growing evidence that exposure to certain phthalates may accelerate reproductive aging in women. Women with higher urinary concentrations of select phthalate metabolites also had accelerated age-related declines in ovarian reserve, with evidence of exposure thresholds for MiBP and MCOP.