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      Follow-Up Study of Adolescents Exposed to Di(2-Ethylhexyl) Phthalate (DEHP) as Neonates on Extracorporeal Membrane Oxygenation (ECMO) Support

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          Abstract

          Di(2-ethylhexyl) phthalate (DEHP) is used to make polyvinyl chloride (PVC) plastic tubing soft and flexible. Animal data show that adverse effects of DEHP exposure may include reduced fertility, reduced sperm production in males, and ovarian dysfunction in females. Known treatments that involve high DEHP exposures are blood exchange transfusions, extracorporeal membrane oxygenation (ECMO), and cardiovascular surgery. Although potential exposure to DEHP in ECMO patients is significant, the exposure has not been associated with short-term toxicity. To evaluate long-term toxicity, we undertook a study of neonatal ECMO survivors to assess their onset of puberty and sexual maturity. We evaluated 13 male and 6 female subjects at 14–16 years of age who had undergone ECMO as neonates. All subjects had a complete physical examination including measurements for height, weight, head circumference, and pubertal assessment by Tanner staging. The testicular volume and the phallic length were measured in male participants. Laboratory tests included thyroid, liver, and renal function as well as measurements of luteinizing hormone, follicle-stimulating hormone, testosterone for males, and estradiol for females. Except for one patient with Marfan syndrome, the rest had normal growth percentile for age and sex. All had normal values for thyroid, liver, and renal functions. Sexual hormones were appropriate for the stage of pubertal maturity. Our results indicate that adolescents exposed to significant quantities of DEHP as neonates showed no significant adverse effects on their physical growth and pubertal maturity. Thyroid, liver, renal, and male and female gonadal functions tested were within normal range for age and sex distribution.

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          Validation of a self-administered instrument to assess stage of adolescent development.

          Drawings were made from Tanner's photographs illustrating five stages of development each for male genitalia, testicular size, male pubic hair, female breasts, and female pubic hair. Forty-seven females and forty-eight males aged 12-16 years indicated on questionnaires which stage they were most like, and answered other questions related to their physical development. Afterwards they were examined by physicians who had not seen their answers. Pearson correlation coefficients were 0.6 or above for the physician's observations compared with the adolescents' answers for the drawings, with the exception of testicular size. Answers to questions concerning amount of underarm hair and general development also yielded high correlations.
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            The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat.

            Phthalate esters (PE) such as DEHP are high production volume plasticizers used in vinyl floors, food wraps, cosmetics, medical products, and toys. In spite of their widespread and long-term use, most PE have not been adequately tested for transgenerational reproductive toxicity. This is cause for concern, because several recent investigations have shown that DEHP, BBP, DBP, and DINP disrupt reproductive tract development of the male rat in an antiandrogenic manner. The present study explored whether the antiandrogenic action of DEHP occurs by (1) inhibiting testosterone (T) production, or by (2) inhibiting androgen action by binding to the androgen receptor (AR). Maternal DEHP treatment at 750 mg/kg/day from gestational day (GD) 14 to postnatal day (PND) 3 caused a reduction in T production, and reduced testicular and whole-body T levels in fetal and neonatal male rats from GD 17 to PND 2. As a consequence, anogenital distance (AGD) on PND 2 was reduced by 36% in exposed male, but not female, offspring. By GD 20, DEHP treatment also reduced testis weight. Histopathological evaluations revealed that testes in the DEHP treatment group displayed enhanced 3ss-HSD staining and increased numbers of multifocal areas of Leydig cell hyperplasia as well as multinucleated gonocytes as compared to controls at GD 20 and PND 3. In contrast to the effects of DEHP on T levels in vivo, neither DEHP nor its metabolite MEHP displayed affinity for the human androgen receptor at concentrations up to 10 microM in vitro. These data indicate that DEHP disrupts male rat sexual differentiation by reducing T to female levels in the fetal male rat during a critical stage of reproductive tract differentiation.
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              Mechanisms of phthalate ester toxicity in the female reproductive system.

              Phthalates are high-production-volume synthetic chemicals with ubiquitous human exposures because of their use in plastics and other common consumer products. Recent epidemiologic evidence suggests that women have a unique exposure profile to phthalates, which raises concern about the potential health hazards posed by such exposures. Research in our laboratory examines how phthalates interact with the female reproductive system in animal models to provide insights into the potential health effects of these chemicals in women. Here we review our work and the work of others studying these mechanisms and propose a model for the ovarian action of di-(2-ethylhexyl) phthalate (DEHP). In vivo, DEHP (2 g/kg) causes decreased serum estradiol levels, prolonged estrous cycles, and no ovulations in adult, cycling rats. In vitro, monoethylhexyl phthalate (MEHP; the active metabolite of DEHP) decreases granulosa cell aromatase RNA message and protein levels in a dose-dependent manner. MEHP is unique among the phthalates in its suppression of aromatase and in its ability to activate peroxisome proliferator-activated receptors (PPARs). We hypothesize that MEHP activates the PPARs to suppress aromatase in the granulosa cell. MEHP-, PPAR alpha-, and PPAR gamma-specific ligands all similarly decreased estradiol production and RNA message levels of aromatase in vitro. Our model shows that MEHP acts on the granulosa cell by decreasing cAMP stimulated by follicle stimulating hormone and by activating the PPARs, which leads to decreased aromatase transcription. Thus, the environmental contaminant DEHP, through its metabolite MEHP, acts through a receptor-mediated signaling pathway to suppress estradiol production in the ovary, leading to anovulation.
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                Author and article information

                Journal
                Environ Health Perspect
                Environmental Health Perspectives
                National Institue of Environmental Health Sciences
                0091-6765
                September 2004
                7 April 2004
                : 112
                : 13
                : 1339-1340
                Affiliations
                1Departments of Neonatology,
                2Endocrinology, and
                3Transfusion Medicine, Children’s National Medical Center and The George Washington University School of Medicine, Washington, DC, USA
                Author notes
                Address correspondence to K. Rais-Bahrami, Department of Neonatology, Children’s National Medical Center, 111 Michigan Ave., NW, Washington, DC 20010 USA. Telephone: (202) 884-4764. Fax: (202) 884-3459. E-mail: Kraisbah@CNMC.org

                The study was supported by grant M01-RR13297 from the General Clinical Research Center, Program of the National Center for Research Resources, National Institutes of Health, Department of Health and Human Services.

                The authors declare they have no competing financial interests.

                Article
                ehp0112-001339
                10.1289/ehp.6901
                1247527
                15345350
                8d8ddbe6-97bd-4352-a9ae-fded34cd30d7
                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
                : 8 December 2003
                : 7 April 2004
                Categories
                Children's Health
                Articles

                Public health
                dehp,toxicity,ecmo
                Public health
                dehp, toxicity, ecmo

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