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

ObjectiveTo evaluate whether the well-established age-related reduction in antral follicle counts (AFC) is greater among women with higher concentrations of endocrine-disrupting chemicals. DesignProspective 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. SubjectsSeven 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. ExposureAge at AFC assessment calculated as the date of antral follicle scan minus the patients birthdate, categorized into <35 years or [&ge;]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 MeasuresAFC assessed by transvaginal ultrasonography. ResultsIn 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. ConclusionSelect 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. CAPSULEWomen 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.