A Mixture of Five Phthalate Esters Inhibits Fetal Testicular Testosterone Production in the Sprague-Dawley Rat in a Cumulative, Dose-Additive Manner

Howdeshell, Kembra L.; Wilson, Vickie S.; Furr, Johnathan; Lambright, Christy; Rider, Cynthia V.; Blystone, Chad R.; Hotchkiss, Andrew K.; Gray, L. Earl

doi:10.1093/toxsci/kfn077

Cited by 375 publications

(271 citation statements)

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“…Loss of testicular function is caused by various mechanisms such as antiandrogenic effects of phthalate esters in rats [10] and fish [11], disruption of microtubule dynamics by Sertoli cell toxicants [12][13][14][15][16], disruption of Ca 2+ homeostasis [17], disruption of the blood-testis barrier via the mitogen-activated protein kinase signaling pathway The affected genes were classified into 12 functional categories according to "Gene Ontology".…”

Section: Discussionmentioning

confidence: 99%

“…The present study demonstrated the disruption of all stages of spermatogenesis predicted by histopathological alterations in 3-month-old transgenic rats. These disorders were marked in terms of seminiferous epithelial sloughing, vacuolization and degeneration in spermatocytes in addition to abnormal elongated spermatids and spermatozoa in the seminiferous lumen.cDNA microarray and realtime PCR analyses revealed that the expression levels of four genes (cnot7, fgf7, testin and ostf1) significantly increased (P<0.05) and that those of two genes (versican and mamdc1) decreased (P<0.05).Loss of testicular function is caused by various mechanisms such as antiandrogenic effects of phthalate esters in rats [10] and fish [11], disruption of microtubule dynamics by Sertoli cell toxicants [12][13][14][15][16], disruption of Ca 2+ homeostasis [17], disruption of the blood-testis barrier via the mitogen-activated protein kinase signaling pathway In the epididymides of the transgenic rat, degenerating round spermatids (B1) and many types of abnormal elongated spermatids (B2-4) were frequently observed. Abnormal spermatozoa showing a breakage of surface membranes (B5) and decline in the member of outer dense fiber were also observed (B-6).…”

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confidence: 99%

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Accumulated HSV1-TK Proteins Interfere with Spermatogenesis through a Disruption of the Integrity of Sertoli-Germ Cell Junctions

Katō

Chen

et al. 2012

Journal of Reproduction and Development

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Abstract. Transgenic rats show spermatid-specific ectopic expression of the reporter gene, herpes simplex virus type1 thymidine kinase (HSV1-TK), in the testes and have demonstrated male infertility. However, the disruption of spermatogenesis and the underlying molecular mechanisms in these transgenic animals have not been well clarified. In this study, light and electron microscopic observations were performed to characterize the morphological changes in the testes. To explore the molecular mechanisms of male infertility in the HSV1-TK transgenic rat, cDNA microarray and quantitative real-time PCR analyses were performed. The seminiferous tubules of 3-month-old transgenic rats showed morphological alterations including seminiferous epithelial sloughing, vacuolization, and degeneration of spermatogenic cells, suggesting a failure of Sertoli-germ cell interaction. Components of the epididymal lumen from transgenic rats included abnormal spermatozoa, degenerating round spermatids and abnormal elongated spermatids indicating an appearance of direct impairment of spermiogenesis. cDNA microarray and real-time PCRanalyses revealed significant changes (P<0.05) in the gene expression level in six genes, testin, versican, mamdc1, fgf7, ostf1 and cnot7. Among them, testin drew most of our attention, since the testin gene is a sensitive marker for disruption of Sertoli-germ cell adhesion. Thus, our results suggest that the accumulation of HSV1-TK in the spermatids not only directly interferes with spermiogenesis but also disrupts spermatogenesis through a disruption of Sertoligerm cell adhesions. It is important to explore the testicular actions of the HSV1-TK protein in transgenic experimental models and thereby gain clues to find an appropriate treatment for HSV-infected patients exhibiting human male infertility, as has been recently observed. Key words: HSV1-TK, Infertility, Spermatogenesis, Testin, Transgenic rat (J. Reprod. Dev. 58: [544][545][546][547][548][549][550][551] 2012) A suicide gene system, herpes simplex virus type 1 thymidine kinase (HSV1-TK) and its specific substrate, ganciclovir, is widely used for cancer therapy [1,2]. However, previous investigators also reported that HSV1-TK proteins are likely to play a toxic role in the developing mouse male germ cells in the absence of the nucleoside analog, ganciclovir, to induce defects in cell proliferation [3][4][5][6]. The major histological defects of HSV1-TK transgenic mice appeared to be an abnormal nuclear morphology of elongating spermatids and electron microscopy observation disclosed insufficient chromatin condensation and abnormal acrosome structures [4]. Al-Shawi et al. demonstrated that truncated TK polypeptides are translated mainly in the haploid spermatids by a cryptic TATA box-independent promoter and that the severity of male infertility depended on the level of enzymatic activity of HSV1-TK produced [5]. However, precise morphological analyses of the seminiferous tubules of HSV1-TK transgenic mice have not yet been reported.We previously ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Accumulated HSV1-TK Proteins Interfere with Spermatogenesis through a Disruption of the Integrity of Sertoli-Germ Cell Junctions

Katō

Chen

et al. 2012

Journal of Reproduction and Development

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“…The environmental agents that cause these effects often have many modes of action, but for simplicity, they are here described as being estrogenic or anti-androgenic. For both classes of compounds, it has also been shown that they can act together to produce effects at doses that individually are not associated with any observable responses (Silva et al 2002, Howdeshell et al 2008, Christiansen et al 2009. A majority of in vivo mixture studies have tested the combinations of anti-androgenic compounds and although the doses applied in these experiments have been in the range of no-observed-adverse-effect levels (NOAELs), they were still quite far from environmental exposures experienced by humans.…”

Section: Introductionmentioning

confidence: 99%

“…This cumulative risk assessment method assumes that the joint action of mixture components can be approximated by dose addition, and that antagonisms or synergisms are not relevant , a conjecture that is supported by empirical evidence , Howdeshell et al 2008, Christiansen et al 2009). The method uses NOAELs or benchmark doses of the individual components as input values, together with the dose of each component present in the mixture.…”

Section: Introductionmentioning

confidence: 99%

Mixtures of endocrine-disrupting contaminants induce adverse developmental effects in preweaning rats

et al. 2014

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Reproductive toxicity was investigated in rats after developmental exposure to a mixture of 13 endocrine-disrupting contaminants, including pesticides, plastic and cosmetic ingredients, and paracetamol. The mixture was composed on the basis of information about high-end human exposures, and the dose levels reflecting 100, 200, and 450 times this exposure were tested. The compounds were also grouped according to their estrogenicity or anti-androgenicity, and their joint effects were tested at two different doses, with each group reflecting 200 or 450 times human exposure. In addition, a single paracetamol dose was tested (350 mg/kg per day). All exposures and a vehicle were administered by oral gavage to time-mated Wistar dams rats throughout gestation and lactation, and their offspring were assessed for reproductive effects at birth and in prepuberty. The mixture doses, which included the anti-androgenic compounds, affected the male offspring by causing decreased anogenital distance, increased nipple retention (NR), and reduced ventral prostate weights, at both medium and high doses. In addition, the weights of the levator ani/bulbocavernosus muscle (LABC) were decreased at the high dose of anti-androgen mixture. No effects were seen after exposure to the estrogenic chemicals alone, whereas males exposed solely to paracetamol showed decreased LABC weights and increased NR. Thus adverse reproductive effects were observed at mixtures reflecting 200 times high-end human exposure, which is relatively close to the safety margin covered by the regulatory uncertainty factor of 100. This suggests that highly exposed human population groups may not be sufficiently protected against mixtures of endocrine-disrupting chemicals.

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“…It decreases testicular testosterone production and caused fetal mortality due to pregnancy loss (12).…”

Section: Diisobutyl Phthalatementioning

confidence: 99%

Ovarian development in Wistar rat treated prenatally with single dose diisobutyl phthalate

Ray¹,

D’Souza²,

Kumar³

et al. 2013

BLL

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Abstract:Phthalates are a class of industrial compounds with an array of toxicological properties used in day to day life. Diisobutyl phthalate on (DIBP) is used as an additive to keep the plastics soft or fl exible (plasticizer) in nitrocellulose plastic, nail polish, explosives, lacquer manufacturing etc. Although DIBP exposure in humans is generally low, people in adhesive industries and pharmaceutical industries are exposed to higher levels. The aim of this study was to determine the effect of single dose of DIBP on developing ovary of Wistar rat. One hundred and eight adult pregnant Wistar rats were divided into control and experimental groups. Rats in experimental group were given DIBP on day 10, 12 and 14 of gestation at 0.375, 0.75 and 1.25 ml/kg body weight dose intraperitoneally in a single dose. Sections of ovaries collected on day 21 of gestation were stained with hematoxylin and eosin and examined and Masson's trichrome histologically. Sections belonging to the control group showed the presence of oocytes in clusters separated by thin fi brous septa. Degeneration oocytes, empty follicles surrounded by follicular cells without gonocytes in the center were observed in ovarian stroma. Blood vessels in the ovarian stroma were prominent and congested. Around a bunch of follicles total architectural disarray was observed although on special staining fi brosis was not evident. As pregnant women are constantly exposed, effect of DIBP on ovary of a developing fetus would denote the long term consequence in future generations (Fig. 5, Ref. 39 Phthalates are a class of widely used industrial compounds known technically as dialkyl or alkyl aryl esters of 1, 2-benzenedicarboxylic acid. The common forms of phthalates are Diethyl hexyl phthalate (DHEP), Diallyl phthalates (DAP), Di-n-propyl phthalates (DPP), Di-n-butyl phthalates (DBP), and Diisobutyl phthalates (DIBP).Phthalates with a variety of toxicological properties are used in day to day life. These phthalates are nearly omnipresent in modern society and are found in the plastic items, vinyl fl ooring, wall coverings, lubricants, adhesives, detergents, nail polish, hair spray and car wash (1).The adverse effects produced by phthalates are changes in morphology, physiology, growth, development or life span of an organism which results in an impairment of functional capacity and ability to compensate for additional stress (2). Diisobutyl phthalateDIBP (phthalic acid ,di isobutyl ester 1,2-benzenedicarboxylic acid ,bis-(2-methyl propyl) ester di-(isobutyl)-1,2-benzene dicarboxylate) is the branched isomer of DBP and an additive used to keep the plastics soft or more fl exible (plasticizer) often in combination with other phthalates. DIBP is used in nitrocellulose plastic, nail polish, explosive materials, lacquer manufacturing, consumer products, blood bags, pharmaceuticals and automobile parts. They are ubiquitous in our environment and most people including pregnant women and their fetuses are exposed to multiple phthalates at a time. Saillenfait et al estim...

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A Mixture of Five Phthalate Esters Inhibits Fetal Testicular Testosterone Production in the Sprague-Dawley Rat in a Cumulative, Dose-Additive Manner

Cited by 375 publications

References 39 publications

Accumulated HSV1-TK Proteins Interfere with Spermatogenesis through a Disruption of the Integrity of Sertoli-Germ Cell Junctions

Accumulated HSV1-TK Proteins Interfere with Spermatogenesis through a Disruption of the Integrity of Sertoli-Germ Cell Junctions

Mixtures of endocrine-disrupting contaminants induce adverse developmental effects in preweaning rats

Ovarian development in Wistar rat treated prenatally with single dose diisobutyl phthalate

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