{"doi":"10.64898/2025.12.09.25341902","title":"Environmental Chemicals as Modifiers of the Association between Age and Ovarian Reserve","abstract":"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.","journal":"medRxiv","year":2025,"id":584954,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9677,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":471278,"name":"Edward H. Kennedy","orcid":"0000-0002-0227-158X","position":1,"is_corresponding":false},{"id":1252930,"name":"Ya‐Hui Yu","orcid":"0000-0002-9104-8899","position":2,"is_corresponding":false},{"id":307047,"name":"Russ Hauser","orcid":"0000-0002-1899-3982","position":3,"is_corresponding":false},{"id":368523,"name":"Lidia Mínguez‐Alarcón","orcid":"0000-0002-2370-3900","position":4,"is_corresponding":false},{"id":428486,"name":"Audrey J. Gaskins","orcid":"0000-0003-0812-7439","position":5,"is_corresponding":false},{"id":369131,"name":"Ashley I. Naimi","orcid":"0000-0002-1510-8175","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:59:16.166424Z","pmid":"41415496","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}