Mesulergine Induced Leydig Cell Tumours, a Syndrome Involving the Pituitary-Testicular Axis of the Rat

Prentice, D. E.; Siegel, Richard A.; Donatsch, P.; Qureshi, S.; Ettlin, Robert A.

doi:10.1007/978-3-642-77260-3_27

Cited by 28 publications

(21 citation statements)

References 16 publications

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“…The eff ect on Prl levels was not observed at the 8-week timepoint, which suggests compensation of the HPG axis by this timepoint. Note that the increase in baseline Prl levels from 2 -8 weeks in controls as seen in this study is typical for young male rats (Prentice et al 1992). It is important to note that the decrease in serum Prl from this 90-day LCT MoA study was not apparent at 100 ppm, which was the mid-dose level, and associated with promotion of LCTs, in the carcinogenicity study.…”

Section: Key Event #2: Decreased Serum Prl Levelssupporting

confidence: 54%

“…For PrlR involvement in LCTs, dopamine agonists, such as muselergine, reduce Prl release by the anterior pituitary gland, which results in a decreased binding to PrlR on Leydig cells (Prentice and Miekle 1995). This decreased PrlR stimulation results in downregulation of LHRs and, therefore, lower T levels, which feeds back to induce LH release from the pituitary leading to Leydig cell stimulation and hyperplasia (Prentice et al 1992). …”

Section: Molecular Basis Of the Diff Erence In Species/strain Incidenmentioning

confidence: 99%

“…Higher serum Prl levels causes downregulation of LHRs within the rat Leydig cells (Prentice et al 1992). Decreased LHR gene expression results in slight decreases in T production, which feeds back to the hypothalamus and pituitary gland to cause a compensatory increase in circulating LH to maintain T at physiologic concentrations (Cook et al 1999).…”

Section: Key Events For Moa #9 (Dopamine Agonism/enhancement)mentioning

confidence: 99%

“…Sulfoxafl or is a known nAChRs partial agonist in insects, which was hypothesized to increase dopaminergic neurotransmission in the tuberoinfundibular system, resulting in increased dopamine release into the hypothalamic portal circulation and inhibition Prl release by the pituitary. The connection has been established with pharmaceutical dopamine agonists (Prentice et al 1992). It is plausible that the LCT promotion seen in the rat chronic/carcinogenicity study was through subtle, but prolonged, agonism at the central nAChRs within the median eminence causing release of dopamine and inhibition of Prl release from the pituitary gland.…”

Section: Key Event #1: Increased Dopamine Release Via Nachr Agonismmentioning

confidence: 99%

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Mode-of-action and human relevance framework analysis for rat Leydig cell tumors associated with sulfoxaflor

Rasoulpour¹,

Terry²,

LeBaron³

et al. 2014

Critical Reviews in Toxicology

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(2014) Mode-of-action and human relevance framework analysis for rat Leydig cell tumors associated with sulfoxaflor, Critical Reviews in Toxicology, 44:sup2, 25-44, DOI: 10.3109/10408444.2014 AbstractSulfoxafl or, a molecule that targets sap-feeding insects, was assessed for carcinogenic potential in groups of 50 Fischer rats fed with diets containing 0, 25, 100, 500 (males), or 750 (females) ppm sulfoxafl or for 2 years according to OECD 453. Sulfoxafl or did not alter the number of rats with Leydig cell tumors (LCTs: 88% of controls and 90 -92% in treated groups). The size of LCT was increased at 100 and 500 ppm. The spontaneous incidence of LCT in Fischer rat is 75 -100% compared with less than 0.01% in humans. These fundamental interspecies diff erences in spontaneous incidence of LCT are the result of quantitative and qualitative diff erences in Leydig cell response to hormonal stimuli. There are nine known modes of actions (MoA) for LCT induction. Analysis sulfoxafl or data suggested a hormone-based dopamine enhancement MoA causing the LCT eff ect through: 1) increased neuronal dopamine release via specifi c dopaminergic neuronbased nicotinic acetylcholine receptor (nAChR) agonism, leading to 2) decreased serum prolactin (Prl) levels, 3) downregulation of luteinizing hormone receptor (LHR) gene expression in Leydig cells, 4) transient decreases in serum testosterone, 5) increased serum LH levels, and 6) promotion of LCTs. The analysis suggested that sulfoxafl or promoted LCTs through a subtle stimulation of dopamine release. The MoA for LCT promotion in the carcinogenicity study is considered to have no relevance to humans due to qualitative and quantitative diff erences between rat and human Leydig cells. Therefore, the Fischer 344 rat LCT promotion associated with lifetime administration of high-dose levels of sulfoxafl or would not pose a cancer hazard to humans.

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Section: Key Event #2: Decreased Serum Prl Levelssupporting

confidence: 54%

Section: Molecular Basis Of the Diff Erence In Species/strain Incidenmentioning

confidence: 99%

Section: Key Events For Moa #9 (Dopamine Agonism/enhancement)mentioning

confidence: 99%

Section: Key Event #1: Increased Dopamine Release Via Nachr Agonismmentioning

confidence: 99%

See 2 more Smart Citations

Mode-of-action and human relevance framework analysis for rat Leydig cell tumors associated with sulfoxaflor

Rasoulpour¹,

Terry²,

LeBaron³

et al. 2014

Critical Reviews in Toxicology

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“…The differential diagnosis between LC hyperplasia and adenoma is basically challenging, as proliferative LCs are usually cytologically not different from normal LCs except for large tumors (Ettlin et al 1992). The differentiation between normal, hyperplastic and neoplastic LCs is, therefore, often arbitrary and generally based on the size of a lesion.…”

Section: Introductionmentioning

confidence: 99%

RITA—Registry of Industrial Toxicology Animal data: The application of historical control data for Leydig cell tumors in rats

Nolte

Rittinghausen

Kellner

et al. 2011

Experimental and Toxicologic Pathology

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Historical data for Leydig cell tumors from untreated or vehicle treated rats from carcinogenicity studies collected in the RITA database are presented. Examples are given for analyses of these data for dependency on variables considered to be of possible influence on the spontaneous incidence of Leydig cell tumors.In the 7453 male rats available for analysis, only one case of a Leydig cell carcinoma was identified. The incidence of Leydig cell adenomas differed markedly between strains. High incidences of close to 100% have been found in F344 rats, while the mean incidence was 4.2% in Sprague Dawley rats and 13.7% in Wistar rats. Incidences in Wistar rats were highly variable, primarily caused by different sources of animals. Mean incidences per breeder varied from 2.8% to 39.9%.Analyses for the dependency on further parameters have been performed in Wistar rats. In breeders G and I, the Leydig cell tumor incidence decreased over the observation period and with increasing mean terminal body weight. The incidence of Leydig cell tumors increased with mean age at necropsy and was higher in studies with dietary admixture compared to gavage studies. These parameters had no effect on Leydig cell tumor incidence in breeders A and B. Animals from almost all breeders had a considerably higher mean age at necropsy when bearing a Leydig cell adenoma than animals without a Leydig cell adenoma. Studies with longitudinal trimming of the testes had a higher incidence than studies with transverse trimming.The observed dependencies and breeder differences are discussed and explanations are given.Consequences for the use of historical control data are outlined. With the retrospective Page 3 of 43 A c c e p t e d M a n u s c r i p t Nolte et al: RITA -The application of historical control data for Leydig cell tumors in rats -3 -analyses presented here we were able to confirm the published features of Leydig cell adenomas and carcinomas. This indicates that the RITA database is a valuable tool for analyses of tumors for their biological features. Furthermore, it demonstrates that the RITA database is highly beneficial for the definition of reliable historical control data for carcinogenicity studies on a scientifically solid basis.

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Human Relevance of Rodent Leydig Cell Tumors

Steinbach¹,

Maronpot²,

Hardisty³

2015

Hamilton &Amp; Hardy's Industrial Toxicology

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Mesulergine Induced Leydig Cell Tumours, a Syndrome Involving the Pituitary-Testicular Axis of the Rat

Cited by 28 publications

References 16 publications

Mode-of-action and human relevance framework analysis for rat Leydig cell tumors associated with sulfoxaflor

Mode-of-action and human relevance framework analysis for rat Leydig cell tumors associated with sulfoxaflor

RITA—Registry of Industrial Toxicology Animal data: The application of historical control data for Leydig cell tumors in rats

Human Relevance of Rodent Leydig Cell Tumors

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