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Synergistic Disruption of External Male Sex Organ Development by a Mixture of Four Antiandrogens

Environmental health perspectives, 2009-12, Vol.117 (12), p.1839-1846 [Peer Reviewed Journal]

COPYRIGHT 2009 National Institute of Environmental Health Sciences ;Copyright National Institute of Environmental Health Sciences Dec 2009 ;2009 ;ISSN: 0091-6765 ;EISSN: 1552-9924 ;DOI: 10.1289/ehp.0900689 ;PMID: 20049201

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Title:
Synergistic Disruption of External Male Sex Organ Development by a Mixture of Four Antiandrogens
Author: Christiansen, Sofie ; Scholze, Martin ; Dalgaard, Majken ; Vinggaard, Anne Marie ; Axelstad, Marta ; Kortenkamp, Andreas ; Hass, Ulla
Subjects: Androgen antagonists ; Androgen Antagonists - toxicity ; Animals ; Antiandrogens ; Chemical hazards ; Chemical mixtures ; Diethylhexyl Phthalate - toxicity ; Dosage ; Dose response relationship ; Dose-Response Relationship, Drug ; Drug Synergism ; Finasteride - toxicity ; Genital diseases, Male ; Genitalia ; Genitalia, Male - abnormalities ; Genitalia, Male - drug effects ; Health aspects ; Hypospadias ; Imidazoles - toxicity ; Male ; Nipples ; No-Observed-Adverse-Effect Level ; Organ Size - drug effects ; Oxazoles - toxicity ; Phthalates ; Physiological aspects ; Rats ; Rats, Wistar ; Reproductive organs, Male ; Risk factors ; Sex Differentiation - drug effects
Is Part Of: Environmental health perspectives, 2009-12, Vol.117 (12), p.1839-1846
Description: Background: By disrupting the action of androgens during gestation, certain chemicals present in food, consumer products, and the environment can induce irreversible demasculinization and malformations of sex organs among male offspring. However, the consequences of simultaneous exposure to such chemicals are not well described, especially when they exert their actions by differing molecular mechanisms. Objectives: To fill this gap, we investigated the effects of mixtures of a widely used plasticizer, di(2-ethylhexyl) phthalate (DEHP); two fungicides present in food, vinclozolin and prochloraz; and a pharmaceutical, finasteride, on landmarks of male sexual development in the rat, including changes in anogenital distance (AGD), retained nipples, sex organ weights, and malformations of genitalia. These chemicals were chosen because they disrupt androgen action with differing mechanisms of action. Results: Strikingly, the effect of combined exposure to the selected chemicals on malformations of external sex organs was synergistic, and the observed responses were greater than would be predicted from the toxicities of the individual chemicals. In relation to other hallmarks of disrupted male sexual development, including changes in AGD, retained nipples, and sex organ weights, the combined effects were dose additive. When the four chemicals were combined at doses equal to no observed adverse effect levels estimated for nipple retention, significant reductions in AGD were observed in male offspring. Conclusions: Because unhindered androgen action is essential for human male development in fetal life, these findings are highly relevant to human risk assessment. Evaluations that ignore the possibility of combination effects may lead to considerable underestimations of risks associated with exposures to chemicals that disrupt male sexual differentiation.
Publisher: United States: National Institute of Environmental Health Sciences
Language: English
Identifier: ISSN: 0091-6765
EISSN: 1552-9924
DOI: 10.1289/ehp.0900689
PMID: 20049201
Source: US Government Documents
MEDLINE
PubMed Central
ProQuest Central
DOAJ Directory of Open Access Journals

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Synergistic Disruption of External Male Sex Organ Development by a Mixture of Four Antiandrogens

COPYRIGHT 2009 National Institute of Environmental Health Sciences ;Copyright National Institute of Environmental Health Sciences Dec 2009 ;2009 ;ISSN: 0091-6765 ;EISSN: 1552-9924 ;DOI: 10.1289/ehp.0900689 ;PMID: 20049201

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