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      Human Exposure to Endocrine-Disrupting Chemicals and Prenatal Risk Factors for Cryptorchidism and Hypospadias: A Nested Case–Control Study

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          Abstract

          Background

          Exposure to xenoestrogens during pregnancy may disturb the development and function of male sexual organs.

          Objective

          In this study we aimed to determine whether the combined effect of environmental estrogens measured as total effective xenoestrogen burden (TEXB) is a risk factor for male urogenital malformations.

          Methods

          In a case–control study, nested in a mother–child cohort ( n = 702) established at Granada University Hospital, we compared 50 newborns with diagnosis of cryptorchidism and/or hypospadias with 114 boys without malformations matched by gestational age, date of birth, and parity. Controls did not differ from the total cohort in confounding variables. TEXB and levels of 16 organochlorine pesticides were measured in placenta tissues. Characteristics of parents, pregnancy, and birth were gathered by questionnaire. We used conditional and unconditional regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

          Results

          TEXB from organohalogenated compounds was detectable in 72% and 54% of case and control placentas, respectively. Compared with controls, cases had an OR for detectable versus non-detectable TEXB of 2.82 (95% CI, 1.10–7.24). More pesticides were detected in cases than in controls (9.34 ± 3.19 vs. 6.97 ± 3.93). ORs for cases with detectable levels of pesticides, after adjusting for potential confounders in the conditional regression analysis, were o,p′-DDT (OR = 2.25; 95% CI, 1.03–4.89), p,p′-DDT (OR = 2.63; 95% CI, 1.21–5.72), lindane (OR = 3.38; 95% CI, 1.36–8.38), mirex (OR = 2.85; 95% CI, 1.22–6.66), and endosulfan alpha (OR = 2.19; 95% CI, 0.99–4.82). Engagement of mothers in agriculture (OR = 3.47; 95% CI, 1.33–9.03), fathers’ occupational exposure to xenoestrogens (OR = 2.98; 95% CI, 1.11–8.01), and history of previous stillbirths (OR = 4.20; 95% CI, 1.11–16.66) were also associated with risk of malformations.

          Conclusions

          We found an increased risk for male urogenital malformations related to the combined effect of environmental estrogens in placenta.

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          Most cited references58

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          Obesity: preventing and managing the global epidemic

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            The E-SCREEN assay as a tool to identify estrogens: an update on estrogenic environmental pollutants.

            Estrogens are defined by their ability to induce the proliferation of cells of the female genital tract. The wide chemical diversity of estrogenic compounds precludes an accurate prediction of estrogenic activity on the basis of chemical structure. Rodent bioassays are not suited for the large-scale screening of chemicals before their release into the environment because of their cost, complexity, and ethical concerns. The E-SCREEN assay was developed to assess the estrogenicity of environmental chemicals using the proliferative effect of estrogens on their target cells as an end point. This quantitative assay compares the cell number achieved by similar inocula of MCF-7 cells in the absence of estrogens (negative control) and in the presence of 17 beta-estradiol (positive control) and a range of concentrations of chemicals suspected to be estrogenic. Among the compounds tested, several "new" estrogens were found; alkylphenols, phthalates, some PCB congeners and hydroxylated PCBs, and the insecticides dieldrin, endosulfan, and toxaphene were estrogenic by the E-SCREEN assay. In addition, these compounds competed with estradiol for binding to the estrogen receptor and increased the levels of progesterone receptor and pS2 in MCF-7 cells, as expected from estrogen mimics. Recombinant human growth factors (bFGF, EGF, IGF-1) and insulin did not increase in cell yields. The aims of the work summarized in this paper were a) to validate the E-SCREEN assay; b) to screen a variety of chemicals present in the environment to identify those that may be causing reproductive effects in wildlife and humans; c) to assess whether environmental estrogens may act cumulatively; and finally d) to discuss the reliability of this and other assays to screen chemicals for their estrogenicity before they are released into the environment.
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              Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries.

              Several investigators have shown striking differences in semen quality and testicular cancer rate between Denmark and Finland. Since maldescent of the testis is a shared risk factor for these conditions we undertook a joint prospective study for the prevalence of congenital cryptorchidism. 1068 Danish (1997-2001) and 1494 Finnish boys (1997-99) were consecutively recruited prenatally. We also established prevalence data for all newborns at Turku University Central Hospital, Finland (1997-99, n=5798). Testicular position was assessed by a standardised technique. All subtypes of congenital cryptorchidism were included, but retractile testes were considered normal. Prevalence of cryptorchidism at birth was 9.0% (95% CI 7.3-10.8) in Denmark and 2.4% (1.7-3.3) in Finland. At 3 months of age, prevalence rates were 1.9% (1.2-3.0) and 1.0% (0.5-1.7), respectively. Significant geographic differences were still present after adjustment for confounding factors (birthweight, gestational age, being small for gestational age, maternal age, parity, mode of delivery); odds ratio (Denmark vs Finland) was 4.4 (2.9-6.7, p<0.0001) at birth and 2.2 (1.0-4.5, p=0.039) at three months. The rate in Denmark was significantly higher than that reported 40 years ago. Our findings of increasing and much higher prevalence of congenital cryptorchidism in Denmark than in Finland contribute evidence to the pattern of high frequency of reproductive problems such as testicular cancer and impaired semen quality in Danish men. Although genetic factors could account for the geographic difference, the increase in reproductive health problems in Denmark is more likely explained by environmental factors, including endocrine disrupters and lifestyle.
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                Author and article information

                Journal
                Environ Health Perspect
                Environmental Health Perspectives
                National Institute of Environmental Health Sciences
                0091-6765
                December 2007
                8 June 2007
                : 115
                : S-1
                : 8-14
                Affiliations
                [1 ] Laboratory of Medical Investigations, San Cecilio University Hospital, Granada, Spain
                [2 ] Department of Pediatrics, San Cecilio University Hospital, Granada, Spain
                [3 ] Department of Gynecology and Obstetrics, San Cecilio University Hospital, Granada, Spain
                [4 ] Department of Nutrition, University of Granada, Granada, Spain
                Author notes
                Address correspondence to M.F. Fernandez at the Laboratory of Medical Investigations, San Cecilio University Hospital, 18071-Granada, Spain. Telephone: 34-958-242864. Fax: 34-958-249953. E-mail: marieta@ 123456ugr.es

                M.F.F. and B.O. contributed equally to this article.

                The authors declare they have no competing financial interests.

                Article
                ehp0115s1-000008
                10.1289/ehp.9351
                2174399
                18174944
                121195f9-e30b-42cb-952e-7a46e08f258d
                This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.
                History
                : 22 May 2006
                : 30 October 2006
                Categories
                Monograph

                Public health
                environmental estrogens,risk factors,endocrine-disrupting chemicals,cryptorchidism,hypo-spadias,occupational exposure

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