Time- and Dose-Related Effects of Di-(2-ethylhexyl) Phthalate and Its Main Metabolites on the Function of the Rat Fetal Testis in Vitro

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Abstract

Background

Endocrine-disrupting effects of phthalates are understood primarily from in utero exposures within the fetal rat testis. Nevertheless, their path of action, dose–response character, and cellular target(s) within the fetal testis are not known.

Objectives

In this study we investigated the effects of di-(2-ethylhexyl) phthalate (DEHP), mono-(2-ethylhexyl) phthalate (MEHP), and several of their metabolites on the development of organo-cultured testes from rat fetus.

Methods

We removed testes from 14.5-day-old rat fetuses and cultured them for 1–3 days with or without DEHP, MEHP, and the metabolites.

Results

DEHP (10 ⁻⁵ M) produced a proandrogenic effect after 3 days of culture, whereas MEHP disrupted testis morphology and function. Leydig cells were the first affected by MEHP, with a number of them being inappropriately located within some seminiferous tubules. Additionally, we found a time- and dose-dependent reduction of testosterone. By 48 hr, gonocyte proliferation had decreased, whereas apoptosis increased. Sertoli cell number was unaffected, although some cells appeared vacuolated, and production of anti-Müllerian hormone decreased in a time- and dose-dependent manner. The derived metabolite mono-(2-ethyl-5-hydroxyhexyl) phthalate was the only one to cause deleterious effects to the rat fetal testis in vitro.

Conclusion

We hope that this in vitro method will facilitate the study of different phthalate esters and other endocrine disruptors for direct testicular effects.

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Most cited references 58

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Phthalates, alkylphenols, pesticides, polybrominated diphenyl ethers, and other endocrine-disrupting compounds in indoor air and dust.

Ruthann A Rudel, David E Camann, John Spengler … (2003)

Chemicals identified as endocrine-disrupting compounds (EDCs) have widespread consumer uses, yet little is known about indoor exposure. We sampled indoor air and dust in 120 homes, analyzing for 89 organic chemicals identified as EDCs. Fifty-two compounds were detected in air and 66 were detected in dust. These are the first reported measures in residential environments for over 30 of the compounds, including several detected at the highest concentrations. The number of compounds detected per home ranged from 13 to 28 in air and from 6 to 42 in dust. The most abundant compounds in air included phthalates (plasticizers, emulsifiers), o-phenylphenol (disinfectant), 4-nonylphenol (detergent metabolite), and 4-tert-butylphenol (adhesive) with typical concentrations in the range of 50-1500 ng/m3. The penta- and tetrabrominated diphenyl ethers (flame retardants) were frequently detected in dust, and 2,3-dibromo-1-propanol, the carcinogenic intermediate of a flame retardant banned in 1977, was detected in air and dust. Twenty-three pesticides were detected in air and 27 were detected in dust, the most abundant being permethrins and the synergist piperonyl butoxide. The banned pesticides heptachlor, chlordane, methoxychlor, and DDT were also frequently detected, suggesting limited indoor degradation. Detected concentrations exceeded government health-based guidelines for 15 compounds, but no guidelines are available for 28 compounds, and existing guidelines do not consider endocrine effects. This study provides a basis for prioritizing toxicology and exposure research for individual EDCs and mixtures and provides new tools for exposure assessment in health studies.

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What are the sources of exposure to eight frequently used phthalic acid esters in Europeans?

Matthias Wormuth, Martin Scheringer, Meret Vollenweider … (2006)

Phthalic acid esters (phthalates) are used as plasticizers in numerous consumer products, commodities, and building materials. Consequently, phthalates are found in human residential and occupational environments in high concentrations, both in air and in dust. Phthalates are also ubiquitous food and environmental contaminants. An increasing number of studies sampling human urine reveal the ubiquitous phthalate exposure of consumers in industrialized countries. At the same time, recent toxicological studies have demonstrated the potential of the most important phthalates to disturb the human hormonal system and human sexual development and reproduction. Additionally, phthalates are suspected to trigger asthma and dermal diseases in children. To find the important sources of phthalates in Europeans, a scenario-based approach is applied here. Scenarios representing realistic exposure situations are generated to calculate the age-specific range in daily consumer exposure to eight phthalates. The scenarios demonstrate that exposure of infant and adult consumers is caused by different sources in many cases. Infant consumers experience significantly higher daily exposure to phthalates in relation to their body weight than older consumers. The use of consumer products and different indoor sources dominate the exposure to dimethyl, diethyl, benzylbutyl, diisononyl, and diisodecyl phthalates, whereas food has a major influence on the exposure to diisobutyl, dibutyl, and di-2-ethylhexyl phthalates. The scenario-based approach chosen in the present study provides a link between the knowledge on emission sources of phthalates and the concentrations of phthalate metabolites found in human urine.

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Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism.

Michael Hutchison, M Fisken, Richard Sharpe … (2008)

Becoming a phenotypic male is ultimately determined by androgen-induced masculinization. Disorders of fetal masculinization, resulting in hypospadias or cryptorchidism, are common, but their cause remains unclear. Together with the adult-onset disorders low sperm count and testicular cancer, they can constitute a testicular dysgenesis syndrome (TDS). Although masculinization is well studied, no unifying concept explains normal male reproductive development and its abnormalities, including TDS. We exposed rat fetuses to either anti-androgens or androgens and showed that masculinization of all reproductive tract tissues was programmed by androgen action during a common fetal programming window. This preceded morphological differentiation, when androgen action was, surprisingly, unnecessary. Only within the programming window did blocking androgen action induce hypospadias and cryptorchidism and altered penile length in male rats, all of which correlated with anogenital distance (AGD). Androgen-driven masculinization of females was also confined to the same programming window. This work has identified in rats a common programming window in which androgen action is essential for normal reproductive tract masculinization and has highlighted that measuring AGD in neonatal humans could provide a noninvasive method to predict neonatal and adult reproductive disorders. Based on the timings in rats, we believe the programming window in humans is likely to be 8-14 weeks of gestation.

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Author and article information

Journal

Journal ID (nlm-ta): Environ Health Perspect

Title: Environmental Health Perspectives

Publisher: National Institute of Environmental Health Sciences

ISSN (Print): 0091-6765

ISSN (Electronic): 1552-9924

Publication date (Print): April 2009

Publication date (Electronic): 1 December 2008

Volume: 117

Issue: 4

Pages: 515-521

Affiliations

[1 ] INSERM (Institut National de la Santé et de la Recherche Médicale), U625, GERHM, Université Rennes I, Campus de Beaulieu, Rennes, France;

[2 ] UMR FLAVIC, ENSBANA (Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l’Alimentation), Dijon, France;

[3 ] ARKEMA France, Département Toxicologie et Environnement, Colombes, France;

[4 ] Institut und Poliklinik für Arbeits-, Sozial- und Umweltmedizin, Erlangen, Germany

Author notes

Address correspondence to B. Jégou, INSERM, U625, GERHM, Campus de Beaulieu, Université Rennes I, Rennes, Bretagne F-35042 France. Telephone: 33-0-2-23-23-69-11, Fax: 33-0-2-23-23-50-55, E-mail: Bernard.jegou@ 123456inserm.fr

[*]

These authors contributed equally to this work.

J.F.R. is employed by ARKEMA France, which has three business segments: vinyl products (i.e. chlorine, polyvinyl chloride, and vinyl compounds), industrial chemicals (i.e., acrylics and fluorochemicals), and performance products (i.e., functional additives and technical polymers). The remaining authors declare they have no competing financial interests.

Article

Publisher ID: ehp-117-515

DOI: 10.1289/ehp.11870

PMC ID: 2679593

PubMed ID: 19440488

SO-VID: 8a1380dd-e2ef-44ea-9d19-cf32333822e6

Copyright © 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.

Time- and Dose-Related Effects of Di-(2-ethylhexyl) Phthalate and Its Main Metabolites on the Function of the Rat Fetal Testis in Vitro

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Abstract

Background

Objectives

Methods

Results

Conclusion

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Global Health Next Generation Network

Most cited references 58

Phthalates, alkylphenols, pesticides, polybrominated diphenyl ethers, and other endocrine-disrupting compounds in indoor air and dust.

What are the sources of exposure to eight frequently used phthalic acid esters in Europeans?

Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism.

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