In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin

Mably, Thomas A.; Bjerke, Donald L.; Moore, Robert W.; Gendron‐Fitzpatrick, Annette; Peterson, Richard E.

doi:10.1016/0041-008x(92)90103-y

Cited by 343 publications

(96 citation statements)

References 34 publications

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“…118 Animals exposed to TCDD in utero have been reported to have decreased spermatogenesis. 119 Exposure to TCDD often results in hypothyroidism in animals. This abnormal thyroid activity possibly relates to the manifestation of a spectrum of pathological conditions encountered in TCDD-exposed animals.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Health Impact of Polychlorinated Dibenzo-p-dioxins: A Critical Review

Mukerjee

1998

Journal of the Air & Waste Management Association

122

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Polychlorinated dibenzo-p-dioxins (PCDDs), commonly known as dioxins, form as unwanted impurities in the manufacturing of chlorophenol and its derivatives-pulp and paper-and in the combustion of municipal, sewagesludge, hospital, and hazardous waste. Combustion, in presence of a chlorine donor, seems to be a major source of these compounds. High levels of dioxins are also emitted from metallurgical industries including copper smelters, electric furnaces in steel mills, and wire reclamation incinerators. Trace levels are detectable in emissions from motor vehicles using leaded gasoline or diesel fuel, in forest fires, and in residential wood burning.Extremely persistent and widely distributed in the environment, PCDDs have been detected in all three primary and many secondary media. Releases into the air occur mainly from combustor emissions. Atmospheric dispersion, deposition, and subsequent accumulation in the food chain seem to be the major pathways of exposure to the general population. Residues of these chemicals have been detected in soil, sediment, fish, meat, cow's milk, human adipose tissue, and mothers' milk. In general, these chemicals have high lipophilicity. The elimination half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in humans is approximately 7-11 years.Very little human toxicity data from exposure to PCDDs are available. Health-effect data obtained from occupational settings in humans are based on exposure to chemicals contaminated with TCDD. It produces a spectrum of toxic effects in animals and is one of the most toxic chemicals known. Most of the toxicity data available on TCDD are from high-dose oral exposures to animals. Very few percutaneous and no inhalation exposure data are available in the literature. There is a wide range of difference in sensitivity to PCDD lethality in animals. The signs and symptoms of poisoning with chemicals contaminated with TCDD in humans are analogous to those observed in animals. Dioxin exposures to humans are associated with increased risk of severe skin lesions such as chloracne and hyperpigmentation, altered liver function and lipid metabolism, general weakness associated with drastic weight loss, changes in activities of various liver enzymes, depression of the immune system, and endocrine-and nervous-system abnormalities. It is a potent teratogenic and fetotoxic chemical in animals. A very potent promoter in rat liver carcinogenesis, TCDD also causes cancers of the liver and other organs in animals.

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Section: Mechanisms Of Actionmentioning

confidence: 99%

Health Impact of Polychlorinated Dibenzo-p-dioxins: A Critical Review

Mukerjee

1998

Journal of the Air & Waste Management Association

122

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“…Its effect on the male reproductive system has been widely discussed, and many such effects are reported in rodents exposed to TCDD: reduced testis and sex accessory gland weight, impaired spermatogenesis, decreased ejaculation, and decreased plasma androgen concentrations. [7][8][9] Since maternal TCDD exposure in rodents could similarly affect the perinatal androgenic status in male offspring in utero and during lactation, 8,[10][11][12][13] the effects on future generations are worrisome. The probability of developing any one of these disorders varies greatly with dose, length of exposure, and, most importantly, the species exposed, 1) making it difficult to determine the TCDD threshold for toxicity.…”

Section: Introductionmentioning

confidence: 99%

Proteome Analysis of the Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin on Murine Testicular Leydig and Sertoli Cells.

Uchida

Ohashi

Morikawa

et al. 2001

JOURNAL OF HEALTH SCIENCE

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We treated testicular cell lines Leydig TM3 and Sertoli TM4 with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and used two-dimensional electrophoresis to investigate the resulting protein alterations. Cells were cultured in a medium containing 10 -5 to 10 nM TCDD for 4 hr, under which condition viability was not affected. Protein expression was compared semi-quantitatively by silver staining, by autoradiography of [35 S] methionine-labeled proteins, and by anti-phosphotyrosine antibody. In TM3, 34 protein spots were altered by TCDD, 26 of which were increased and 8 of which were decreased; in TM4, the amount of total protein appeared to be reduced and 19 protein spots were altered by TCDD, 12 of which were increased and 7 of which were decreased. Four of these altered proteins were identified by N-terminal protein microsequencing and by a homology search against protein databases. Whereas a pyruvate dehydrogenase E1 beta subunit was decreased by TCDD exposure, ATP synthase beta chain, mitochondrial matrix protein P1 and 78 kDa glucose-regulated protein were relatively increased. The precise role of these proteins in TCDD toxicity remains to be determined, but the observed alterations suggest the proteins to be important in the effects of TCDD on testicular cells.

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“…In male rats exposed in utero or lactationally (Moore et al, 1985;Mably et al, 1992;Theobald and Peterson, 1997), TCDD decreases growth of the testis, epididymis, and accessory sex organs (seminal vesicles and prostate), alters testicular and epididymal morphology, decreases daily and ejaculated sperm numbers, and impairs reproductive performance. These TCDD effects have been attributed to decreases in circulating androgen levels caused by alterations in enzymes that catalyze testosterone synthesis or its conversion to DHT in androgen target tissues or by a reduction in Leydig cell number, size, and function (Johnson et al, 1992).…”

mentioning

confidence: 99%

2,3,7,8-Tetrachlorodibenzo-p-dioxin Blocks Androgen-Dependent Cell Proliferation of LNCaP Cells through Modulation of pRB Phosphorylation

Barnes-Ellerbe

Knudsen²,

Puga

2004

Mol Pharmacol

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Cell-cycle regulatory events associated with inhibition of androgen-dependent cell proliferation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied in the human-derived LNCaP cell line. TCDD blocked the G 1 to S transition of LNCaP cells synchronized in G 0 /G 1 when these cells were induced to reinitiate cell-cycle progression by dihydrotestosterone (DHT). Western blot analyses of these cells revealed altered expression levels of G 1 regulatory proteins, including increases in hypophosphorylated retinoblastoma protein and concomitant decreases in cyclin D1. p21 WAF1/CIP1 , which is involved in the assembly of cyclin D1/cyclin-dependent kinase-4 complexes, was increased by DHT or TCDD when each compound was administered singly but was reduced to background levels in cells simultaneously treated with DHT and TCDD. Reporter gene assays revealed the presence of several Ah receptor response-element motifs in the promoter and first intron of the p21 WAF1/CIP1 gene that respond to TCDD-mediated Ah receptor activation independently of p53. Transcription studies showed that activation of aryl hydrocarbon receptor blocks androgen-dependent gene induction in LNCaP cells as well as in African green monkey CV-1 cells. These data point to at least two mechanisms whereby TCDD blocks androgen receptor function: 1) by blocking androgen-induced cell proliferation through modulation of the expression and activities of regulatory proteins controlling cell-cycle progression; and 2) by squelching androgen receptor-mediated gene transcription through receptor cross-talk, possibly involving competition for coregulators or by direct protein interaction.Depending on cell type and lineage, exposure to TCDD often leads to multiple diverse responses, including changes in cell proliferation and differentiation. Most, if not all, of the effects of TCDD are mediated through binding to a ligandactivated transcription factor known as the Ah receptor. In brief, TCDD binds to the AHR and facilitates the release of bound 90-kDa heat-shock proteins, resulting in receptor activation. Subsequent to this release, liganded AHR translocates to the nucleus, in which it heterodimerizes with ARNT.

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In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin

Cited by 343 publications

References 34 publications

Health Impact of Polychlorinated Dibenzo-p-dioxins: A Critical Review

Health Impact of Polychlorinated Dibenzo-p-dioxins: A Critical Review

Proteome Analysis of the Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin on Murine Testicular Leydig and Sertoli Cells.

2,3,7,8-Tetrachlorodibenzo-p-dioxin Blocks Androgen-Dependent Cell Proliferation of LNCaP Cells through Modulation of pRB Phosphorylation

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