Testicular germ cell cancer (TGCC) is hypothesized to originate from disruptions of fetal testis development, potentially caused by environmental chemicals. One potential risk factor is 4-hydroxychlorothalonil (4-OH-CHT), a primary transformation product of fungicide chlorothalonil, which is banned across the European Union.
To investigate maternal serum 4-OH-CHT concentrations during pregnancy and the association with TGCC risk in male offspring.
In a nested case-control study (103 TGCC cases, 446 matched controls), we quantified 4-OH-CHT in 549 maternal serum samples using LC-MS/MS. Samples were collected from pregnant women in Denmark during 1985-1994, when chlorothalonil was extensively used. Male offspring were followed (28-38 years) for TGCC diagnoses in the Danish Cancer Registry. Hazard ratios (HR) were estimated using Cox regression.
4-OH-CHT was detected above LOD in all serum samples (median: 1.56 ng/mL). Median concentrations were relatively stable during the 1980s, approximately doubled during the 1990s, and generally peaked in spring. The HR for overall TGCC was 0.89 (95% CI: 0.66-1.21) per doubling of concentrations, with higher risk estimates for nonseminomas and lower for seminomas, although confidence intervals crossed unity. By sample period, the risk was highest among offspring with 1990s samples (HR 1.63, 95% CI: 0.87; 3.06).
Serum 4-OH-CHT was detectable in all investigated pregnant women from Denmark during 1985-1994, with increasing temporal trends. No overall association was observed between maternal serum 4-OH-CHT and TGCC risk in male offspring. However, analyses restricted to 1990s pregnancies, when concentrations were higher, suggested increased TGCC risk, particularly for nonseminomas.
Environmental research. 2026 Jul 24 [Epub ahead of print]
Cecilie S Uldbjerg, Christian Lindh, David M Kristensen, Youn-Hee Lim, Jørgen H Petersen, Karina M Sørensen, Panu Rantakokko, Brent A Coull, Elvira V Bräuner, Russ Hauser, Niels E Skakkebæk, Anders Juul, Lærke Priskorn
Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, University of Copenhagen, Denmark; International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark. Electronic address: ., Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden., Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, University of Copenhagen, Denmark; International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Roskilde University, Department of Science and Environment, Roskilde, Denmark., Section of Environmental Health, Department of Public Health, University of Copenhagen, Copenhagen, Denmark., Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, University of Copenhagen, Denmark; International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Section of Biostatistics, Department of Public Health, University of Copenhagen, Denmark., Danish National Biobank, Statens Serum Institut, Denmark., Department of Public Health, Finnish Institute for Health and Welfare, 70701 Kuopio, Finland., Department of Biostatistics, T.H. Chan School of Public Health, Harvard University, USA., Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, University of Copenhagen, Denmark; International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark., Department of Environmental Health, T.H. Chan School of Public Health, Harvard University, USA., Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, University of Copenhagen, Denmark; International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.