Association of placenta organotin concentrations with congenital cryptorchidism and reproductive hormone levels in 280 newborn boys from Denmark and Finland

Abstract

Is the placental burden of organotin compounds (OTCs) associated with congenital cryptorchidism in infant offspring from Finland and Denmark? Increasing concentrations of OTCs had a negative association with cryptorchidism in Finland, whereas a positive association was found in Denmark. The rapid increase in the prevalence of cryptorchidism suggests that environmental factors, such as endocrine disruptors, may be involved. OTCs are endocrine disruptors at very low concentrations due to activation of the retinoid X receptor (RXR). Between the years 1997 and 2001, placentas from mothers of cryptorchid boys and from healthy controls were collected from Denmark (39 cases, 129 controls) and Finland (56 cases, 56 controls). In Denmark 33 and 6 boys, and in Finland 22 and 34 boys had mild or severe cryptorchidism, respectively. The association between concentrations of four OTCs [monobutyltin (MBT), dibutyltin (DBT), tributyltin (TBT) and triphenyltin (TPhT)] and case-control status was estimated. In both countries, placenta samples were selected from larger cohorts. In Finland placenta samples were collected from boys with cryptorchidism at birth and matched controls (nested case-control design). Matching criteria were parity, maternal smoking (yes/no), diabetes (yes/no), gestational age (±7 days) and date of birth (±14 days). Numbers of controls per case was 1. In Denmark, all available placentas from cryptorchid boys were chosen and control placentas were selected randomly from the total Danish cohort (case-cohort design). The average number of controls per case was 3.3. OTCs in placenta samples were analysed with liquid extraction, ethylation and gas chromatography-mass spectrometry determination and coded by country-specific tertiles. Generally, the concentrations of OTCs were very low. For most analytes, a large proportion of samples (29-96% depending on the country and case-control status) had OTC concentrations below the limit of quantification (LOQ). As an exception, the concentration of TBT was >LOQ in 99% of Finnish placentas. The mean concentrations of DBT and TBT were 1.5 and 7 times higher in Finland than in Denmark, respectively. For DBT in Danish placentas, the odds ratio (OR) for cryptorchidism in the second tertile (0.10-0.14 ng/g) when compared with the first tertile (<0.10 ng/g, <LOQ) was 3.13 (95% CI 1.19-8.26) and the OR for the third tertile (≥0.15 ng/g) when compared with the first tertile was 4.01 (95% CI 1.42-11.33). For TBT in Finnish placentas, the OR for cryptorchidism in the second tertile (0.10-0.39 ng/g) when compared with the first tertile (<0.1 ng/g) was 0.61 (95% CI 0.18-2.01) and the OR for the third tertile (≥0.40 ng/g) when compared with the first tertile was 0.13 (95% CI 0.03-0.54). The main limitation of the study was the relatively small number of mother-boy pairs that limits the extrapolation of the study results to the general population. Also misclassification of exposure is a reason for caution for two reasons: because the concentrations of most OTCs were below or only barely above the LOQ in a large proportion of samples and because it is not known how well OTCs measured from placenta represent exposure at the time window that is relevant for cryptorchidism occurrence. This is the first study to measure the concentrations of OTCs from human placenta samples, and to associate these concentrations to cryptorchidism. As opposite results were obtained with regard to OTC concentration in placenta and cryptorchidism status in Finland and Denmark, and no mechanism is known at the moment by which OTCs could affect testicular descent, these results cannot be generalized to other populations. However, some animal tests described in the literature show opposite effects of OTCs on fat deposition at different ranges of exposure. It is also clearly shown in the literature that TBT has an impact on sexual development of gastropods through RXR. As TBT is known to activate human RXR, further laboratory studies should be designed to explore the potential impact of TBT on male sexual development.