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Original Article
Prenatal exposure to glycol ethers and cryptorchidism and hypospadias: a nested case–control study
  1. Charline Warembourg1,2,
  2. Jérémie Botton3,4,
  3. Nathalie Lelong5,
  4. Florence Rouget1,2,6,
  5. Babak Khoshnood5,
  6. Florent Le Gléau7,
  7. Christine Monfort1,2,
  8. Laurence Labat8,
  9. Fabrice Pierre9,
  10. Barbara Heude3,
  11. Rémy Slama10,
  12. Luc Multigner1,2,
  13. Marie-Aline Charles3,
  14. Sylvaine Cordier1,
  15. Ronan Garlantézec1,2,11
  1. 1 Exposure Assessment and Epidemiological Research on Environment, Reproduction and Development, INSERM UMR 1085 IRSET, Rennes, France
  2. 2 Université de Rennes I, Rennes, France
  3. 3 Center for Epidemiology and Statistics Sorbonne Paris Cité, INSERM UMR 1153, Team: Early Origin of the Child’s Health and Development, Paris Descartes University, Villejuif, France
  4. 4 Faculty of Pharmacy, University Paris Saclay, Malabry, France
  5. 5 Center for Epidemiology and Statistics Sorbonne Paris Cité, DHU Risks in Pregnancy, INSERM UMR 1153, Team: Obstetrical, Perinatal and Pediatric Epidemiology Research, Paris Descartes University, Paris, France
  6. 6 Department of Pediatrics, University Hospital of Rennes, Brittany Registry of Congenital Malformations, Rennes, France
  7. 7 LABOCEA Laboratory, Plouzane, France
  8. 8 Laboratoire de Pharmacologie Toxicologie, Assistance Publique-Hôpitaux de Paris, Groupe Cochin, Paris, France
  9. 9 Service de Gynécologie Obstétrique et Médecine de la Reproduction, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
  10. 10 Department of Environmental Epidemiology, INSERM, CNRS, University Grenoble-Alpes, IAB Institute of Advanced Biosciences Joint Research Center (U1209), Grenoble, France
  11. 11 Service de Santé Publique et d’Epidemiologie, Centre Hospitalo-Universitaire de Rennes, Rennes, France
  1. Correspondence to Dr Charline Warembourg, Inserm UMR 1085 Irset, 9 Avenue du Pr. Léon Bernard, 35000 Rennes, France; charline.warembourg{at}


Objectives Glycol ethers (GE) are oxygenated solvents frequently found in occupational and consumer products. Some of them are well-known testicular and developmental animal toxicants. This study aims to evaluate the risk of male genital anomalies in association with prenatal exposure to GE using urinary biomarkers of exposure.

Methods We conducted a case–control study nested in two joint mother–child cohorts (5303 pregnant women). Cases of cryptorchidism and hypospadias were identified at birth and confirmed during a 2-year follow-up period (n=14 cryptorchidism and n=15 hypospadias). Each case was matched to three randomly selected controls within the cohorts for region of inclusion and gestational age at urine sampling. Concentrations of five GE acidic metabolites were measured in spot maternal urine samples collected during pregnancy. ORs were estimated with multivariate conditional logistic regressions including a Firth’s penalisation.

Results Detection rates of urinary GE metabolites ranged from 8% to 93% and only two were sufficiently detected (>33%) in each cohort to be studied: methoxyacetic acid (MAA) and phenoxyacetic acid (PhAA). A significantly higher risk of hypospadias was associated with the highest tertile of exposure to MAA: OR (95% CI) 4.5(1.4 to 23.4). No association were observed with urinary concentration of PhAA, nor with the risk of cryptorchidism.

Conclusions In view of the toxicological plausibility of our results, this study, despite its small sample size, raises concern about the potential developmental toxicity of MAA on the male genital system and calls for thorough identification of current sources of exposure to MAA.

  • glycol ethers
  • hypospadias
  • cryptorchidism
  • congenital anomalies

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  • Contributors CW: contributed to the study design, statistical analyses, interpretation of data and drafting the manuscript. JB and RFS: contributed to the study design and interpretation of data. NL, FR and BK: responsible for the assessment of male genital anomalies. LM: contributed to the selection of glycol ether, interpretation of data and assisted in drafting the manuscript. FLG and LL: contributed to the measurement of the glycol ethers. FP: contributed to the acquisition of medical data. M-AC and BH: established the EDEN cohort and contributed to the interpretation of data. CM and FR: contributed to the establishment of the PELAGIE cohort and the acquisition of data. SC established the PELAGIE cohort, contributed to the interpretation of data and assisted in drafting the manuscript. RG: initiated the study, contributed to the interpretation of data and assisted in drafting the manuscript. All authors: revised the manuscript critically and approved the final version.

  • Funding This study is funded by the French Agency for Medicines and Health Products Safety (ANSM, APP-2012-080). The PELAGIE cohort is funded by INSERM, the French Ministries of Health, Labour, and Ecology, InVS, ANR and ANSES. The EDEN cohort is funded by FRM, INSERM, IReSP, INPES, Nestlé, the French Ministry of Health, ANR, Paris-Sud University, InVS, ANSES, ALFEDIAM and MGEN.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval CNIL, CCTIRS.

  • Provenance and peer review Not commissioned; externally peer reviewed.