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Genital anomalies in boys and the environment

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The prevalence of male reproductive disorders, such as testicular cancer and impaired semen quality, is increasing in many, albeit not all, countries. These disorders are aetiologically linked with congenital cryptorchidism and hypospadias by common factors leading to perinatal disruption of normal testis differentation, the testicular dysgenesis syndrome (TDS). There is recent evidence that also the prevalence of genital malformations is increasing and the rapid pace of increase suggests that lifestyle factors and exposure to environmental chemicals with endocrine disrupting properties may play a role. Recent prospective studies have established links between perinatal exposure to persistent halogenated compounds and cryptorchidism, as well as between phthalates and anti-androgenic effects in newborns. Maternal alcohol consumption, mild gestational diabetes and nicotine substitutes were also identified as potential risk factors for cryptorchidism. It may be the cocktail effect of many simultaneous exposures that result in adverse effects, especially during foetal life and infancy.

Section snippets

Geographical differences and temporal trends in the prevalence of genital malformations in newborn boys

In accordance with the TDS hypothesis, the increase in the prevalence of adult male reproductive disorders and their geographic distribution corresponds to observations regarding congenital malformations in newborn boys, such as cryptorchidism and hypospadias. Thus, the rate of testis cancer in a given population appears to be a ‘whistle blower’ for the general reproductive health of the male population.10 Registries for genital malformations are, however, not as robust as registries for

Environmental chemicals and their effects on male reproductive development

Cryptorchidism and hypospadias are part of many syndromes with multiple congenital malformations and family clustering has been reported. A few genetic reasons have been identified.40, 41 However, it has been difficult in large series to identify specific genetic mutations or polymorphisms as the cause of cryptorchidism or hypospadias in a significant proportion of patients. Thus, in the majority of clinical cases no distinct aetiology can be established.

Evidence from wildlife observations and

Lifestyle factors and their impact on male genital development

In addition to well-known maternal and foetal risk factors for genital malformations, such as low birth weight, prematurity and pregnancy complications, our prospective cohort study observed a novel risk factor for cryptorchidism,75 that is, the use of nicotine patches of mothers who wished to stop smoking during pregnancy (Table 1). The mechanisms behind this observation are unclear, but in the Danish National Birth Cohort, an increased risk of malformations in the musculoskeletal system was

Cocktail effects of combined exposures

Recent research in animals indicates that there are low-dose mixture effects of chemicals.90 Cocktail exposures of animals at doses, which individually do not produce adverse effects, resulted in a high frequency of genital malformations and testicular impairment in the offspring.91 A few human studies have attempted to assess the effects of combined exposures, although these studies also point towards the possibility that the combined exposure rather than a single compound results in an

Conclusion

Current evidence supports the hypothesis that the aetiology of male genital malformations is multifactorial. Several risk factors may have to be present in combination to result in cryptorchidism or hypospadias. However, there is now also evidence to support the hypothesis that apparently healthy newborn boys may show subtle adverse effects in their genital development, either as reduced testis growth or as altered hormonal production. In addition, some studies also report associations between

Conflicts of interest

All authors declare that they have no conflicts of interest.

Acknowledgement

Research related to this review has been funded by the European Commission (Envir.Reprod.Health, EXPORED, EDEN, DEER), The Danish Medical Research Council, Svend Andersen's Foundation, Velux Foundation, the Danish Network on Endocrine Disrupters (DAN-ED), the Novo Nordisk Foundation, the Academy of Finland, the Sigrid Jusélius Foundation, Finnish Paediatric Research Foundation and The Turku University Hospital. The sponsors had no part in study design, data collection and analysis, writing of

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