Genetic and environmental origins of hypospadias.
OBJECTIVE
The purpose of this study was to review and comment on recent original presentations dealing with genetic and environmental factors in the cause of hypospadias.


RESULTS
The heritability is definitely high and having an affected family member is the highest identified risk factor so far. Many candidate genes and polymorphisms have been suggested for hypospadias. Some associations with hypospadias were found, and many of these were replicated inconsistently as would be expected in a complex disorder affected by both genes and environment. The consistent association of hypospadias with low birth weight, maternal hypertension, and preeclampsia suggests that placental insufficiency is a major risk factor. Maternal exposure to chemical pollutants or endocrine disruptors in high concentrations related to selected occupations or geographic areas may be additional risk factors for hypospadias, especially in genetically predisposed individuals. So far, however, no environmental chemical pollutants or endocrine disruptor with a general common impact on the risk for hypospadias in most societies has been demonstrated.


CONCLUSIONS
A major point that should be considered regarding the action of environmental toxicants in inducing hypospadias is the cumulative effects of multiple low-dose exposures. Furthermore, interactions between genetic and environmental factors may help to explain nonreplication in genetic studies of hypospadias.
aDepartment of Pediatric Surgery, Rigshospitalet bFaculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark cDepartment of Women's and Children's Health, Pediatric Surgery Unit and Center for Molecular Medicine, Karolinska Institutet dPediatric Surgery, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden eDepartment of Pediatric Urology, Royal Children's Hospital fDouglas Stephens Surgical Research Laboratory, Murdoch Children's Research Institute, Melbourne gDepartment of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
Jorgen
J
Thorup
Agneta
A
Nordenskjöld
John M
JM
Hutson
D000328:Adult; D000728:Androgens / Q000172:deficiency; D006063:Chorionic Gonadotropin / Q000378:metabolism; D004785:Environmental Pollutants / Q000009:adverse effects*; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D007021:Hypospadias / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics; D007231:Infant, Newborn; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D010927:Placental Insufficiency / Q000209:etiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology / Q000235:genetics*; D012307:Risk Factors
D000728:Androgens; D006063:Chorionic Gonadotropin; D004785:Environmental Pollutants; D047628:Estrogen Receptor alpha