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      Comparative Effects of Di( n-Butyl) Phthalate Exposure on Fetal Germ Cell Development in the Rat and in Human Fetal Testis Xenografts

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          Abstract

          Background

          Phthalate exposure induces germ cell effects in the fetal rat testis. Although experimental models have shown that the human fetal testis is insensitive to the steroidogenic effects of phthalates, the effects on germ cells have been less explored.

          Objectives

          We sought to identify the effects of phthalate exposure on human fetal germ cells in a dynamic model and to establish whether the rat is an appropriate model for investigating such effects.

          Methods

          We used immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction to examine Sertoli and germ cell markers on rat testes and human fetal testis xenografts after exposure to vehicle or di( n-butyl) phthalate (DBP). Our study included analysis of germ cell differentiation markers, proliferation markers, and cell adhesion proteins.

          Results

          In both rat and human fetal testes, DBP exposure induced similar germ cell effects, namely, germ cell loss (predominantly undifferentiated), induction of multinucleated gonocytes (MNGs), and aggregation of differentiated germ cells, although the latter occurred rarely in the human testes. The mechanism for germ cell aggregation and MNG induction appears to be loss of Sertoli cell–germ cell membrane adhesion, probably due to Sertoli cell microfilament redistribution.

          Conclusions

          Our findings provide the first comparison of DBP effects on germ cell number, differentiation, and aggregation in human testis xenografts and in vivo in rats. We observed comparable effects on germ cells in both species, but the effects in the human were muted compared with those in the rat. Nevertheless, phthalate effects on germ cells have potential implications for the next generation, which merits further study. Our results indicate that the rat is a human-relevant model in which to explore the mechanisms for germ cell effects.

          Citation

          van den Driesche S, McKinnell C, Calarrão A, Kennedy L, Hutchison GR, Hrabalkova L, Jobling MS, Macpherson S, Anderson RA, Sharpe RM, Mitchell RT. 2015. Comparative effects of di( n-butyl) phthalate exposure on fetal germ cell development in the rat and in human fetal testis xenografts. Environ Health Perspect 123:223–230;  http://dx.doi.org/10.1289/ehp.1408248

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          Most cited references35

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          Phthalates: toxicology and exposure.

          Ursel Heudorf, Volker Mersch-Sundermann, Jürgen Angerer (2007)
          Phthalates are used as plasticizers in PVC plastics. As the phthalate plasticizers are not chemically bound to PVC, they can leach, migrate or evaporate into indoor air and atmosphere, foodstuff, other materials, etc. Consumer products containing phthalates can result in human exposure through direct contact and use, indirectly through leaching into other products, or general environmental contamination. Humans are exposed through ingestion, inhalation, and dermal exposure during their whole lifetime, including intrauterine development. This paper presents an overview on current risk assessments done by expert panels as well as on exposure assessment data, based on ambient and on current human biomonitoring results. Some phthalates are reproductive and developmental toxicants in animals and suspected endocrine disruptors in humans. Exposure assessment via modelling ambient data give hints that the exposure of children to phthalates exceeds that in adults. Current human biomonitoring data prove that the tolerable intake of children is exceeded to a considerable degree, in some instances up to 20-fold. Very high exposures to phthalates can occur via medical treatment, i.e. via use of medical devices containing DEHP or medicaments containing DBP phthalate in their coating. Because of their chemical properties exposure to phthalates does not result in bioaccumulation. However, health concern is raised regarding the developmental and/or reproductive toxicity of phthalates, even in environmental concentrations.
          Article 0 comments Cited 243 times – based on 0 reviews     Review now
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            The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat.

            C Lambright, B. Abbott, Elle Parks … (2000)
            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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              Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects.

              Ewa Rajpert-De Meyts (2015)
              Carcinoma in situ testis (CIS), also known as intratubular germ cell neoplasia (ITGCN), is a pre-invasive precursor of testicular germ cell tumours, the commonest cancer type of male adolescents and young adults. In this review, evidence supporting the hypothesis of developmental origin of testicular germ cell cancer is summarized, and the current concepts regarding aetiology and pathogenesis of this disease are critically discussed. Comparative studies of cell surface proteins (e.g. PLAP and KIT), some of the germ cell-specific markers (e.g. MAGEA4, VASA, TSPY and NY-ESO-1), supported by studies of regulatory elements of the cell cycle (e.g. p53, CHK2 and p19-INK4d) demonstrated a close similarity of CIS to primordial germ cells and gonocytes, consistent with the pre-meiotic origin of CIS. Recent gene expression profiling studies showed that CIS cells closely resemble embryonic stem cells (ESCs). The abundance of factors associated with pluripotency (NANOG and OCT-3/4) and undifferentiated state (AP-2gamma) may explain the remarkable pluripotency of germ cell neoplasms, which are capable of differentiating to various somatic tissue components of teratomas. Impaired gonadal development resulting in the arrest of gonocyte differentiation and retention of its embryonic features, associated with an increasing genomic instability, is the most probable model for the pathogenesis of CIS. Genomic amplification of certain chromosomal regions, e.g. 12p, may facilitate survival of CIS and further invasive progression. Genetic studies, have so far not identified gene polymorphisms predisposing to the most common non-familial testicular cancer, but this research has only recently begun. Association of CIS with other disorders, such as congenital genital malformations and some forms of impaired spermatogenesis, all rising in incidence in a synchronous manner, led to the hypothesis that CIS might be a manifestation of testicular dysgenesis syndrome (TDS). The aetiology of TDS including testicular cancer remains to be elucidated, but epidemiological trends suggest a primary role for environmental factors, probably combined with genetic susceptibility.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Environ Health Perspect
                Journal ID (iso-abbrev): Environ. Health Perspect
                Journal ID (publisher-id): EHP
                Title: Environmental Health Perspectives
                Publisher: NLM-Export
                ISSN (Print): 0091-6765
                ISSN (Electronic): 1552-9924
                Publication date (Electronic): 16 December 2014
                Publication date (Print): March 2015
                Volume: 123
                Issue: 3
                Pages: 223-230
                Affiliations
                [1]MRC Centre for Reproductive Health, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
                Author notes
                Address correspondence to S. van den Driesche, MRC Centre for Reproductive Health, The Queen’s Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. Telephone: 44 (0)131 242 6196. E-mail: s.vandendriesche@ 123456ed.ac.uk
                Article
                Publisher ID: ehp.1408248
                DOI: 10.1289/ehp.1408248
                PMC ID: 4348744
                PubMed ID: 25514601
                SO-VID: f72359b5-88fe-4db4-a04b-510e6e408477
                License:

                Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, “Reproduced with permission from Environmental Health Perspectives”); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright.

                History
                Date received : 08 February 2014
                Date accepted : 12 December 2014
                Date: 16 December 2014
                Date: 01 March 2015
                Categories
                Subject: Research

                ScienceOpen disciplines: Public health
                Data availability:
                ScienceOpen disciplines: Public health

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