Concentrations of 4-hydroxychlorothalonil in serum from pregnant women and the association with risk of testicular germ cell cancer in their male offspring

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INTRODUCTION: 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. OBJECTIVE: To investigate maternal serum 4-OH-CHT concentrations during pregnancy and the association with TGCC risk in male offspring. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

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