Journal ArticleDOI
Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat.
Cynthia J. Wolf,Christy S. Lambright,Peter C. Mann,Matthew Price,Ralph L. Cooper,Joseph S. Ostby,L. Earl Gray +6 more
TLDR
The analysis indicates that the chemicals discussed here can be clustered into three or four separate groups, based on the resulting profiles of reproductive effects, and suggests that L may display several mechanisms of endocrine toxicity, one of which involves AR binding.Abstract:
Antiandrogenic chemicals alter sexual differentiation by a variety of mechanisms, and as a consequence, they induce different profiles of effects. For example, in utero treatment with the androgen receptor (AR) antagonist, flutamide, produces ventral prostate agenesis and testicular nondescent, while in contrast, finasteride, an inhibitor of 5 alpha-dihydrotestosterone (DHT) synthesis, rarely, if ever, induces such malformations. In this regard, it was recently proposed that dibutyl phthalate (DBP) alters reproductive development by a different mechanism of action than flutamide or vinclozolin (V), which are AR antagonists, because the male offsprings display an unusually high incidence of testicular and epididymal alterations--effects rarely seen after in utero flutamide or V treatment. In this study, we present original data describing the reproductive effects of 10 known or suspected anti-androgens, including a Leydig cell toxicant ethane dimethane sulphonate (EDS, 50 mg kg-1 day-1), linuron (L, 100 mg kg-1 day-1), p,p'-DDE (100 mg kg-1 day-1), ketoconazole (12-50 mg kg-1 day-1), procymidone (P, 100 mg kg-1 day-1), chlozolinate (100 mg kg-1 day-1), iprodione (100 mg kg-1 day-1), DBP (500 mg kg-1 day-1), diethylhexyl phthalate (DEHP, 750 mg kg-1 day-1), and polychlorinated biphenyl (PCB) congener no. 169 (single dose of 1.8 mg kg-1). Our analysis indicates that the chemicals discussed here can be clustered into three or four separate groups, based on the resulting profiles of reproductive effects. Vinclozolin, P, and DDE, known AR ligands, produce similar profiles of toxicity. However, p,p'-DDE is less potent in this regard. DBP and DEHP produce a profile distinct from the above AR ligands. Male offsprings display a higher incidence of epididymal and testicular lesions than generally seen with flutamide, P, or V even at high dosage levels. Linuron treatment induced a level of external effects consistent with its low affinity for AR [reduced anogenital distance (AGD), retained nipples, and a low incidence of hypospadias]. However, L treatment also induced an unanticipated degree of malformed epididymides and testis atrophy. In fact, the profile of effects induced by L was similar to that seen with DBP. These results suggest that L may display several mechanisms of endocrine toxicity, one of which involves AR binding. Chlozolinate and iprodione did not produce any signs of maternal or fetal endocrine toxicity at 100 mg kg-1 day-1. EDS produced severe maternal toxicity and a 45% reduction in size at birth, which resulted in the death of all neonates by 5 days of age. However, EDS only reduced AGD in male pups by 15%. Ketoconazole did not demasculinize or feminize males but rather displayed anti-hormonal activities, apparently by inhibiting ovarian hormone synthesis, which resulted in delayed delivery and whole litter loss. In summary, the above in vivo data suggest that the chemicals we studied alter male sexual differentiation via different mechanisms. The anti-androgens V, P, and p,p'-DDE produce flutamide-like profiles that are distinct from those seen with DBP, DEHP, and L. The effects of PCB 169 bear little resemblance to those of any known anti-androgen. Only in depth in vitro studies will reveal the degree to which one can rely upon in vivo studies, like those presented here, to predict the cellular and molecular mechanisms of developmental toxicity.read more
Citations
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Journal ArticleDOI
EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals
Andrea C. Gore,Vesna A. Chappell,Suzanne E. Fenton,Jodi A. Flaws,Angel Nadal,Gail S. Prins,Jorma Toppari,R. T. Zoeller +7 more
TL;DR: A much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, can be much better translated to human health.
Journal ArticleDOI
State of the Science of Endocrine Disrupting Chemicals - 2012
TL;DR: The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of UNEP or WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.
Journal ArticleDOI
Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat.
L. Earl Gray,Joseph S. Ostby,Johnathan Furr,Matthew Price,D.N. Rao Veeramachaneni,Louise G. Parks +5 more
TL;DR: It is hypothesized that the phthalate esters that altered testis function in the pubertal male rat would also alter testisfunction in the fetal male and produce malformations of androgen-dependent tissues and, in summary, DEHP, BBP, and DINP all altered sexual differentiation, whereas DOTP, DEP, or DMP were ineffective at this dose.
Journal ArticleDOI
The Plasticizer Diethylhexyl Phthalate Induces Malformations by Decreasing Fetal Testosterone Synthesis during Sexual Differentiation in the Male Rat
Louise G. Parks,Joe Ostby,Christy R. Lambright,Barbara D. Abbott,Gary R. Klinefelter,Norman J. Barlow,L. Earl Gray +6 more
TL;DR: 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.
Journal ArticleDOI
Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) Induce Epigenetic Transgenerational Inheritance of Obesity, Reproductive Disease and Sperm Epimutations
TL;DR: Observations demonstrate that a mixture of plastic derived compounds, BPA and phthalates, can promote epigenetic transgenerational inheritance of adult onset disease and associated DNA methylation epimutations in sperm.
References
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Evidence for decreasing quality of semen during past 50 years.
TL;DR: There has been a genuine decline in semen quality over the past 50 years, and as male fertility is to some extent correlated with sperm count the results may reflect an overall reduction in male fertility.
Journal ArticleDOI
Persistent DDT metabolite p,p'-DDE is a potent androgen receptor antagonist.
William R. Kelce,Stone Cr,Susan C. Laws,Leon Earl Gray,Jon A. Kemppainen,Elizabeth M. Wilson +5 more
TL;DR: It is reported that the major and persistent DDT metabolite,P,P′-DDE (l,l-dichloro-2,2-bis(P- chlorophenyl)ethylene), has little ability to bind the oestrogen receptor, but inhibits androgen binding to the androgen receptor.
Journal ArticleDOI
A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic.
TL;DR: The current finding that some phthalate compounds and some food additives are weakly estrogenic in vitro, needs to be supported by further studies on their effects in vivo before any conclusions can be made regarding their possible role in the development of these conditions.
Book
Chemically-induced alterations in sexual and functional development : the wildlife/human connection
Theo Colborn,Coralie Clement +1 more
TL;DR: The role of mesenchyme in the development of the urogenital tract was discussed by Howard A. Bern and M.M. van Saal as discussed by the authors, who found evidence of contaminant-induced alterations in sexual development in free-living wildlife.
Journal ArticleDOI
Environmental Hormone Disruptors: Evidence That Vinclozolin Developmental Toxicity Is Mediated by Antiandrogenic Metabolites
TL;DR: As the concentrations of M1 in the serum of pregnant rats and their pups on Postnatal Day 3 meet or exceed the in vitro Ki for androgen receptor inhibition, it is suggested that the demasculinizing effects of vinclozolin exposure in vivo also may be mediated via the antiandrogenic metabolites M1 and/or M2.