Article

Risk factors for hypospadias

Department of Epidemiology and Biostatistics (133), Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
European Journal of Pediatrics (Impact Factor: 1.98). 08/2007; 166(7):671-8. DOI: 10.1007/s00431-006-0304-z
Source: PubMed

ABSTRACT Despite being one of the most common congenital defects in boys, the etiology of hypospadias remains largely unknown. In this case-referent study, we evaluated a wide spectrum of potential risk factors for hypospadias. Cases were identified from the hospital information system, and referents were recruited through the parents of the cases. Both parents of cases and referents completed written questionnaires that they received through the mail. Logistic regression analyses were used to assess the independent contribution of different factors to the risk of hypospadias. The final database included 583 cases and 251 referents. Hypospadias more often occurred in children whose father had hypospadias (OR=9.7; 95%CI: 1.3-74.0) and in children with a low birth weight (OR=2.3; 95%CI: 1.2-4.2). Indications for elevated risks were found when mothers were DES-daughters (OR=3.5; 95%CI: 0.8-15.6), fathers were subfertile (OR=1.8; 95%CI: 0.7-4.5), the parents had undergone fertility treatment (OR=2.3; 95%CI: 0.9-5.8), and in twin or triplet pregnancies (OR=2.0; 95%CI: 0.8-5.1). Maternal use of iron supplements (OR=2.2; 95%CI: 0.8-6.0), maternal smoking (OR=1.5; 95%CI: 1.0-2.4), paternal prescriptive drug use (OR=2.6; 95%CI: 1.1-6.6), and paternal exposure to pesticides (OR=2.1; 95%CI: 0.6-7.1) during the 3 months immediately prior to conception or in the first trimester of pregnancy also appeared to increase the risk of hypospadias. The associations found in this study support the hypothesis that genetic predisposition, placental insufficiency, and substances that interfere with natural hormones play a role in the etiology of hypospadias.

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    • "TOXLET - 8505 ; No . of Pages 7 M . Michalakis et al . / Toxicology Letters xxx ( 2013 ) xxx – xxx 5 Fig . 4 . Scatter plot of the sumDAPs in blood between parents and children with hypospadias . of our study , since familial clustering for male external genital malformations has been already reported ( Brouwers et al . , 2007 ; Gaspari et al . , 2011 ) ."
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    ABSTRACT: We have currently evaluated the possible association between hypospadias and exposure to organophosphorus (OP) and organochlorine (OC) pesticides. For this purpose, we measured the dialkyl phosphate metabolites of organophosphate pesticides (DAPs) in the hair and blood, as well as OC pesticides (DDTs, HCHs) in the hair collected from children with hypospadias and their parents. The concentration of HCHs in the hair samples obtained from mothers was higher than that previously reported for people working in open cultivations, while the concentration of DDTs in the hair samples obtained from mothers, fathers and their children with hypospadias was much higher than that previously reported for occupationally exposed individuals. The DMP concentration in hair samples obtained from mothers was much higher not only from that reported for the general population, but even higher than that reported for occupationally exposed individuals. Furthermore, SUMDEPs and SUMDAPs in the hair samples obtained both from the hypospadiac boys, as well as from their parents were higher than the corresponding values previously reported for the general population. Our study supports the hypothesis that organophosphate and organochlorine pesticide exposure may be a potential risk factor for hypospadias.
    Toxicology Letters 10/2013; 230(2). DOI:10.1016/j.toxlet.2013.10.015 · 3.36 Impact Factor
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    • "This limitation undermines their potential validity. For example, the large studies of Swedish subjects included controls from healthy adult blood volunteers from a local hospital (Beleza-Meireles et al., 2007b), and the large study of Dutch subjects included cases that were likely much younger than controls and recruited from a larger catchment area (Brouwers et al., 2006b; Hoogendoorn et al., 2006; van der Zanden et al., 2010b). "
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    ABSTRACT: This review evaluates current knowledge related to trends in the prevalence of hypospadias, the association of hypospadias with endocrine-disrupting exposures, and the potential contribution of genetic susceptibility to its etiology. The review focuses on epidemiologic evidence. Increasing prevalence of hypospadias has been observed, but such increases tend to be localized to specific regions or time periods. Thus, generalized statements that hypospadias is increasing are unsupported. Owing to the limitations of study designs and inconsistent results, firm conclusions cannot be made regarding the association of endocrine-disrupting exposures with hypospadias. Studies with more rigorous study designs (e.g., larger and more detailed phenotypes) and exposure assessment that encompasses more breadth and depth (e.g., specific endocrine-related chemicals) will be critical to make better inferences about these important environmental exposures. Many candidate genes for hypospadias have been identified, but few of them have been examined to an extent that enables solid conclusions. Further study is needed that includes larger sample sizes, comparison groups that are more representative of the populations from which the cases were derived, phenotype-specific analyses, and more extensive exploration of variants. In conclusion, examining the associations of environmental and genetic factors with hypospadias remain important areas of inquiry, although our actual understanding of their contribution to hypospadias risk in humans is currently limited.
    Birth Defects Research Part A Clinical and Molecular Teratology 07/2012; 94(7):499-510. DOI:10.1002/bdra.23021 · 2.21 Impact Factor
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    • "Last, in a recent meta-analysis of studies from the United States and Europe, Rocheleau et al. (2009) reported that maternal occupational exposure to pesticides was associated with a 36% increased risk of hypospadias relative to the risk in mothers without exposure (risk ratio = 1.36; 95% CI, 1.04–1.77). The risk of developing cryptorchidism (Pierik et al. 2004) and hypospadias (Brouwers et al. 2007) was also associated with paternal exposures to pesticides, mainly in greenhouses for the production of vegetables and flowers. "
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    ABSTRACT: Evidence suggests that there is widespread decline in male reproductive health and that antiandrogenic pollutants may play a significant role. There is also a clear disparity between pesticide exposure and data on endocrine disruption, with most of the published literature focused on pesticides that are no longer registered for use in developed countries. We used estimated human exposure data to select pesticides to test for antiandrogenic activity, focusing on highest use pesticides. We used European databases to select 134 candidate pesticides based on highest exposure, followed by a filtering step according to known or predicted receptor-mediated antiandrogenic potency, based on a previously published quantitative structure-activity relationship (QSAR) model. In total, 37 pesticides were tested for in vitro androgen receptor (AR) antagonism. Of these, 14 were previously reported to be AR antagonists ("active"), 4 were predicted AR antagonists using the QSAR, 6 were predicted to not be AR antagonists ("inactive"), and 13 had unknown activity, which were "out of domain" and therefore could not be classified with the QSAR ("unknown"). All 14 pesticides with previous evidence of AR antagonism were confirmed as antiandrogenic in our assay, and 9 previously untested pesticides were identified as antiandrogenic (dimethomorph, fenhexamid, quinoxyfen, cyprodinil, λ-cyhalothrin, pyrimethanil, fludioxonil, azinphos-methyl, pirimiphos-methyl). In addition, we classified 7 compounds as androgenic. Due to estimated antiandrogenic potency, current use, estimated exposure, and lack of previous data, we strongly recommend that dimethomorph, fludioxonil, fenhexamid, imazalil, ortho-phenylphenol, and pirimiphos-methyl be tested for antiandrogenic effects in vivo. The lack of human biomonitoring data for environmentally relevant pesticides presents a barrier to current risk assessment of pesticides on humans.
    Environmental Health Perspectives 02/2011; 119(6):794-800. DOI:10.1289/ehp.1002895 · 7.98 Impact Factor
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