Synthetic Phenolic Antioxidants and Their Metabolites in Follicular Fluid and Association with Diminished Ovarian Reserve: A Case–Control Study

BACKGROUND: Diminished/decreased ovarian reserve (DOR) is a disorder of ovarian function, which severely affects women’s reproductive health. Accumulating evidence has found that adverse environmental factors can affect ovarian function. However, whether synthetic phenolic antioxidants (SPAs) exposure is associated with DOR is still unknown. OBJECTIVES: We explored whether concentrations of SPAs and their metabolites are associated with DOR. METHODS: A case–control study was conducted from January 2019 to January 2020 in China. One hundred eighty-one women 20–44 years of age, with (case group, [Formula: see text]) and without DOR (control group, [Formula: see text]) were included in our study. The follicular fluid concentrations of typical SPAs and their metabolites were measured, including butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), butylated hydroxytoluene (BHT), and five BHT metabolites [3,5-di-tert-butyl-4-hydroxy-benzylalcohol (BHT-OH), 3,5-di-tert-butyl-4-hydroxybenzaldehyde (BHT-CHO), 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHT-COOH), 2,6-di-tert-butyl-1,4-benzoquinone (BHT-Q), and 2,6-di-tert-butyl-4-hydroxy-4-methylcyclohexa-2,5-dien-1-one (BHT-quinol)]. Information about serum basal concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and anti-Müllerian hormone (AMH) and the basal antral follicle count (AFC) was collected. RESULTS: The measured frequencies of BHA, TBHQ, BHT, BHT-OH, BHT-CHO, BHT-COOH, BHT-Q, and BHT-quinol in follicular fluid were 1.7%, 2.2%, 40.3%, 46.4%, 57.5%, 100%, 64.6%, and 49.2%, respectively. The concentrations of BHT-CHO ([Formula: see text] vs. [Formula: see text] , [Formula: see text]), BHT-COOH ([Formula: see text] vs. [Formula: see text] , [Formula: see text]), BHT-Q ([Formula: see text] vs. [Formula: see text] , [Formula: see text]), and the sum of five BHT metabolites ([Formula: see text]; [Formula: see text] vs. [Formula: see text] , [Formula: see text]) in the case group were significantly higher than those in the control group. The risk of DOR was further analyzed according to the tertiles of chemical concentration. Compared with the low levels of BHT metabolites, the adjusted odds ratios (ORs) for DOR were significantly increased in the high levels of BHT-CHO [[Formula: see text] , 95% confidence interval (CI): 1.22, 8.31, [Formula: see text]], BHT-COOH [[Formula: see text] (95% CI: 1.63, 13.71), [Formula: see text]], and BHT-Q [[Formula: see text] (95% CI: 1.69, 11.86), [Formula: see text]] after adjusting for age, body mass index, education, infertility type, triglycerides, and total cholesterol. Moreover, compared with the low level of [Formula: see text] , increased adjusted ORs for DOR were found both in the middle level [[Formula: see text] (95% CI: 1.44, 11.75), [Formula: see text]] and high level [[Formula: see text] (95% CI: 1.81, 16.77), [Formula: see text]], showing an obvious dose–response relationship ([Formula: see text]). CONCLUSION: In this study, we report the measured frequency and concentrations of BHA, TBHQ, BHT, and their metabolites in follicular fluid. Moreover, we found the concentrations of BHT metabolites, especially BHT-CHO, BHT-COOH, and BHT-Q, are positively associated with the increased risk of DOR. https://doi.org/10.1289/EHP11309