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

Objective: 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. Design: 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. Subjects: 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. Exposure: 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. Main Outcome Measures: AFC assessed by transvaginal ultrasonography. Results: 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. Conclusion: Select phthalate metabolites, specifically MiBP, MCOP, and MEHP, were associated with a modified age-related decline in ovarian reserve in a curvilinear dosedependent manner. These findings add to the growing evidence that exposure to certain phthalates may accelerate reproductive aging in women.