Pre- and Postnatal Oral Toxicity of Vinclozolin in Wistar and Long–Evans Rats

Hellwig, J.; Ravenzwaay, Bennard van; Mayer, Michael; Gembardt, C.

doi:10.1006/rtph.2000.1400

Cited by 65 publications

(33 citation statements)

References 10 publications

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“…For vinclozolin the lowest observed adverse effect level recommended for humans is 11 mg/kg⅐d, but doses at the 1 mg/kg⅐d have biological effects (79). For rats the lowest observed adverse effect level has been reported as 25 mg/kg⅐d (80), whereas the no observable and adverse effect level is reported as 6 mg/ kg⅐d (81). The environmental levels of vinclozolin have not been rigorously determined, such that no conclusions regarding the toxicology of this compound can currently be made.…”

Section: Discussionmentioning

confidence: 96%

Transgenerational Epigenetic Imprinting of the Male Germline by Endocrine Disruptor Exposure during Gonadal Sex Determination

et al. 2006

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Embryonic exposure to the endocrine disruptor vinclozolin at the time of gonadal sex determination was previously found to promote transgenerational disease states. The actions of vinclozolin appear to be due to epigenetic alterations in the male germline that are transmitted to subsequent generations. Analysis of the transgenerational epigenetic effects on the male germline (i.e. sperm) identified 25 candidate DNA sequences with altered methylation patterns in the vinclozolin generation sperm. These sequences were identified and mapped to specific genes and noncoding DNA regions. Bisulfite sequencing was used to confirm the altered methylation pattern of 15 of the candidate DNA sequences. Alterations in the epigenetic pattern (i.e. methylation) of these genes/DNA sequences were found in the F2 and F3 generation germline. Therefore, the reprogramming of the male germline involves the induction of new imprinted-like genes/DNA sequences that acquire an apparent permanent DNA methylation pattern that is passed at least through the paternal allele. The expression pattern of several of the genes during embryonic development were found to be altered in the vinclozolin F1 and F2 generation testis. A number of the imprinted-like genes/DNA sequences identified are associated with epigenetic linked diseases. In summary, an endocrine disruptor exposure during embryonic gonadal sex determination was found to promote an alteration in the epigenetic (i.e. induction of imprinted-like genes/DNA sequences) programming of the male germline, and this is associated with the development of transgenerational disease states.

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Section: Discussionmentioning

confidence: 96%

Transgenerational Epigenetic Imprinting of the Male Germline by Endocrine Disruptor Exposure during Gonadal Sex Determination

et al. 2006

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“…Therefore, endocrine disruptors have the capacity to influence embryonic androgen receptor actions (32,33). Alternatively, vinclozolin actions could involve toxicologic actions on the developing gonad to subsequently influence germ cell development (17,34,35). Further studies are needed to elucidate the endocrine vs. toxicologic actions of vinclozolin on the embryonic testis.…”

Section: Discussionmentioning

confidence: 95%

Endocrine Disruptor Vinclozolin Induced Epigenetic Transgenerational Adult-Onset Disease

2006

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The fetal basis of adult disease is poorly understood on a molecular level and cannot be solely attributed to genetic mutations or a single etiology. Embryonic exposure to environmental compounds has been shown to promote various disease states or lesions in the first generation (F1). The current study used the endocrine disruptor vinclozolin (antiandrogenic compound) in a transient embryonic exposure at the time of gonadal sex determination in rats. Adult animals from the F1 generation and all subsequent generations examined (F1-F4) developed a number of disease states or tissue abnormalities including prostate disease, kidney disease, immune system abnormalities, testis abnormalities, and tumor development (e.g. breast). In addition, a number of blood abnormalities developed including hypercholesterolemia. The incidence or prevalence of these transgenerational disease states was high and consistent across all generations (F1-F4) and, based on data from a previous study, appears to be due in part to epigenetic alterations in the male germ line. The observations demonstrate that an environmental compound, endocrine disruptor, can induce transgenerational disease states or abnormalities, and this suggests a potential epigenetic etiology and molecular basis of adult onset disease.

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“…In adult life, ventral prostate weight is permanently reduced (at 6.25, 25, 50, and 100 mg/kg/d) and male offspring display permanent female-like nipples. Treatment at 50 and 100 mg/kg/d induces hypospadias and other reproductive tract malformations Hellwig et al 2000). The most sensitive period of development to the disruptive effects of vinclozolin is GD 16-17, with less severe effects seen in males exposed to vinclozolin on GD 14-15 and GD 18-19 (Wolf et al 2000).…”

Section: Modes Of Action Of the Individual Chemicals Used In Our Mixtmentioning

confidence: 99%

Cumulative Effects of In Utero Administration of Mixtures of “Antiandrogens” on Male Rat Reproductive Development

Rider

Wilson²,

Howdeshell³

et al. 2009

Toxicol Pathol

101

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Although risk assessments are typically conducted on a chemical-by-chemical basis, the 1996 Food Quality Protection Act (FQPA) required the Environmental Protection Agency (EPA) to consider cumulative risk of chemicals that act via a common mechanism of toxicity. To this end, we are conducting studies with mixtures to provide a framework for assessing the cumulative effects of "antiandrogenic" chemicals. Rats were dosed during pregnancy with antiandrogens singly or in pairs at dosage levels equivalent to about one half of the ED 50 for hypospadias or epididymal agenesis. The pairs include: AR antagonists (vinclozolin plus procymidone), phthalate esters (DBP plus BBP and DEHP plus DBP), a phthalate ester plus an AR antagonist (DBP plus procymidone), and linuron plus BBP. We predicted that each chemical by itself would induce few malformations; however, by mixing any two chemicals together, about 50% of the males would be malformed. All binary combinations produced cumulative, doseadditive effects on the androgen-dependent tissues. We also conducted a mixture study combining seven "antiandrogens" together. These chemicals elicit antiandrogenic effects at two different sites in the androgen signaling pathway (i.e., AR antagonist or inhibition of androgen synthesis). In this study, the complex mixture behaved in a dose-additive manner. Our results indicate that compounds that act by disparate mechanisms of toxicity display cumulative, dose-additive effects when present in combination.

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Pre- and Postnatal Oral Toxicity of Vinclozolin in Wistar and Long–Evans Rats

Cited by 65 publications

References 10 publications

Transgenerational Epigenetic Imprinting of the Male Germline by Endocrine Disruptor Exposure during Gonadal Sex Determination

Transgenerational Epigenetic Imprinting of the Male Germline by Endocrine Disruptor Exposure during Gonadal Sex Determination

Endocrine Disruptor Vinclozolin Induced Epigenetic Transgenerational Adult-Onset Disease

Cumulative Effects of In Utero Administration of Mixtures of “Antiandrogens” on Male Rat Reproductive Development

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