Shao Shanshan, Pan Weijun, Wang Baolin, Liu Yuwei, Gan Hong, Li Mengdie, Liao Tierong, Yang Xinliu, Yang Qianhui, Huang Cun, Geng Menglong, Pan Guixia, Liu Kaiyong, Zhu Peng, Tao Fangbiao
School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, No 81 Meishan Road, Hefei, Anhui, China; Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, No 81 Meishan Road, Hefei, Anhui, China.
Clinical Center of Reproductive Medicine, Ma'anshan Maternal and Child Health Hospital, Ma'anshan, Anhui, China.
Ecotoxicol Environ Saf. 2023 Jan 1;249:114414. doi: 10.1016/j.ecoenv.2022.114414. Epub 2022 Dec 12.
Based on self-report questionnaires, two previous epidemiological studies investigated the association between the exposure of women to antibiotics and their fertility. However, biomonitoring studies on low-dose antibiotic exposure, mainly from food and water, and its relation to the risk of infertility are missing.
Based on a case-control study design, 302 women with infertility (144 primary infertility, 158 secondary infertility) and 302 women with normal fertility, all aged 20-49 years, were recruited from Anhui Province, China, in 2020 and 2021. A total of 41 common antibiotics and two antibiotic metabolites in urine samples were determined by liquid chromatography-triple quadrupole tandem mass spectrometry (LC-QqQ-MS/MS).
Twenty-eight antibiotics with detection rates from 10% to 100% in both cases (median concentration: ∼2.294 ng/mL) and controls (∼1.596 ng/mL) were included in the analysis. Logistic regression analysis revealed that after controlling for confounding factors, high concentrations of eight individual antibiotics (sulfamethoxazole, sulfaclozine, sulfamonomethoxine, penicillin G, chlorotetracycline, ofloxacin, norfloxacin, and cyadox) and four antibiotic classes (sulfonamides, tetracyclines, quinoxalines, and veterinary antibiotics) were related to a high risk of female infertility, with odds ratios (ORs) ranging from 1.30 to 2.86, except for chlorotetracycline (OR = 6.34), while another nine individual antibiotics (sulfamethazine, azithromycin, cefaclor, amoxicillin, oxytetracycline, pefloxacin, sarafloxacin, enrofloxacin, and florfenicol) and classes of chloramphenicol analogs and human antibiotics were related to a reduced risk of infertility, with ORs ranging from 0.70 to 0.20. Based on restricted cubic spline models after controlling for confounding factors, we observed that the relationship between all of the above protective antibiotics and infertility was nonlinear: A certain concentration could reduce the risk of female infertility while exceeding a safe dose could increase the risk of infertility.
These results provide preliminary evidence that the effects of antibiotics on female fertility vary based on the active ingredient and usage and imply the importance of exposure dose. Future studies are needed to verify these results by controlling for multiple confounding factors.
基于自我报告问卷，此前有两项流行病学研究调查了女性接触抗生素与其生育能力之间的关联。然而，关于主要来自食物和水的低剂量抗生素暴露及其与不孕风险关系的生物监测研究尚属空白。
基于病例对照研究设计，2020年和2021年从中国安徽省招募了302名不孕女性（144例原发性不孕，158例继发性不孕）和302名生育能力正常的女性，年龄均在20 - 49岁之间。通过液相色谱 - 三重四极杆串联质谱法（LC - QqQ - MS/MS）测定尿液样本中总共41种常见抗生素和两种抗生素代谢物。
分析纳入了在病例组（中位浓度：约2.294 ng/mL）和对照组（约1.596 ng/mL）中检出率为10%至100%的28种抗生素。逻辑回归分析显示，在控制混杂因素后，高浓度的8种单一抗生素（磺胺甲恶唑、磺胺氯吡嗪、磺胺间甲氧嘧啶、青霉素G、金霉素、氧氟沙星、诺氟沙星和喹乙醇）以及4类抗生素（磺胺类、四环素类、喹喔啉类和兽用抗生素）与女性不孕高风险相关，比值比（OR）范围为1.30至2.86，但金霉素除外（OR = 6.34），而另外9种单一抗生素（磺胺二甲嘧啶、阿奇霉素、头孢克洛、阿莫西林、土霉素、培氟沙星、沙拉沙星、恩诺沙星和氟苯尼考）以及氯霉素类似物和人用抗生素类与不孕风险降低相关，OR范围为0.70至0.20。在控制混杂因素后基于受限立方样条模型，我们观察到上述所有保护性抗生素与不孕之间的关系是非线性的：一定浓度可降低女性不孕风险，而超过安全剂量则会增加不孕风险。
这些结果提供了初步证据，表明抗生素对女性生育能力的影响因活性成分和使用情况而异，并暗示了暴露剂量的重要性。未来需要通过控制多种混杂因素来验证这些结果的研究。
