Mode of action and human relevance of pronamide-induced rat thyroid tumors

Papineni, Sabitha; Marty, M. Sue; Rasoulpour, Reza J.; LeBaron, Matthew J.; Pottenger, Lynn H.; Eisenbrandt, David L.

doi:10.1016/j.yrtph.2015.02.012

Cited by 19 publications

(13 citation statements)

References 28 publications

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“…PB activates CAR (Constitutive androstane receptor) and then is well-known to induce various enzymes including CYP2B and UGT (UDP-glucuronosyltransferase) (Qatanani et al, 2005). UGT enhances metabolism of circulating thyroid hormones such as T3 and T4 by glucuronic acid conjugation and biliary excretion of the conjugated hormone (Meek et al, 2003;Papineni et al, 2015). Therefore, the induction of UGT results in a decrease in T3 and T4 halflife.…”

Section: A B C D E Fmentioning

confidence: 99%

The effects on the endocrine system under hepatotoxicity induction by phenobarbital and di(2-ethylhexyl)phthalate in intact juvenile male rats

et al. 2019

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Phenobarbital (PB) and Di (2-ethylhexyl) phthalate (DEHP), an anti-epileptic drug and a plasticizer used in flexible polyvinylchloride formulations, respectively, are well-known typical hepatotoxicants. This study investigated the effects of PB (100 mg/kg/day) or DEHP (500 mg/kg/day) on the endocrine system in intact juvenile/peripubertal male rats exposed for 31 days beginning on postnatal day 23. Slight hormone level changes, histopathological changes in thyroid gland or induction of UDPglucuronosyltransferase in liver were observed in both the PB and DEHP groups. One of the assumed mechanisms inducing thyroid effects is predictable to be secondary changes based on the enhancement in thyroid hormone metabolism via the induction of hepatic microsomal enzymes. No reproductive systemrelated changes in organ weights, histopathology, and sexual maturation were observed in both groups. Lower testosterone level was observed in the PB group. CYP2B and CYP3A, which are involved in testosterone metabolism, were induced in liver of the PB group. There was no change of 17β-hydroxysteroid dehydrogenase activity in testis of both groups. Lower testosterone level in the PB-treated male rats was attributed to an indirect, hepatotoxicity-associated effect on the reproductive system and not to direct effects on testis such as the antiandrogenic activity and the inhibition of steroidogenesis. These results did not indicate that PB or DEHP exposure affects the endocrine system directly.

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Section: A B C D E Fmentioning

confidence: 99%

The effects on the endocrine system under hepatotoxicity induction by phenobarbital and di(2-ethylhexyl)phthalate in intact juvenile male rats

et al. 2019

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“…Some chemicals are reported to act as thyroid toxicants in rats, causing decreased serum thyroid hormone levels and increased TSH levels, and these changes result in thyroid tumor (Cunha & van Ravenzwaay, ; Montoya et al, ; Papineni et al, ). The MOAs of these chemicals are categorized in two main groups.…”

Section: Introductionmentioning

confidence: 99%

“…As thyroid hormones regulate basic physiologic processes of the whole body, such as development and metabolism, perturbation of thyroid hormone homeostasis may possibly lead to severe endocrine dysfunction (Cheng, Leonard, & Davis, 2010). Some chemicals are reported to act as thyroid toxicants in rats, causing decreased serum thyroid hormone levels and increased TSH levels, and these changes result in thyroid tumor (Cunha & van Ravenzwaay, 2005;Montoya et al, 2014;Papineni et al, 2015). The MOAs of these chemicals are categorized in two main groups.…”

Section: Introductionmentioning

confidence: 99%

Specific alteration of gene expression profile in rats by treatment with thyroid toxicants that inhibit thyroid hormone synthesis

Ôhara

Yamada

Fukuda

et al. 2018

J of Applied Toxicology

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Transcriptomics technologies have been used for risk assessment of chemicals, mainly to predict the modes of action (MOAs) of chemicals or identify biomarkers. Transcriptomics data may also be helpful to understand MOAs of chemicals at the molecular level in more detail. As an example of the known MOAs, there are two MOAs of thyroid toxicity: inhibition of thyroid hormone synthesis ("direct" effect) and hypermetabolism of thyroid hormone by enzyme induction in liver ("indirect" effect). In the present study, global profiles of gene expression were analyzed in rats treated with chemicals acting directly on the thyroid (thyroid peroxidase inhibitors such as propylthiouracil and methimazole) and chemicals acting indirectly on the thyroid (hepatic enzyme inducers such as phenobarbital and pregnenolone-16α-carbonitrile) using microarrays. Using a subtraction method between these two types of chemicals, we identified characteristic gene expression changes on the thyroid hormone synthesis pathway by direct-acting chemicals. Based on the functions of these genes, alterations of their expression seem to indicate the results of thyroid peroxidase inhibition, and might be helpful in more accurate evaluation of MOAs for thyroid toxicity.

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“…This may result in the induction of thyroid follicular cell adenomas and/or carcinomas and testis Leydig cell adenomas (Marty et al 2015). In addition, enhanced hormone production in the pituitary will occur which may escalate to hyperplasia and lead eventually to the formation of pituitary adenomas and/or carcinomas (Papineni et al 2015). Although there is a clear link between the tumor types described here, activation of the CAR/PXR/RXR receptor does not necessarily lead to the formation of tumors in all organs involved.…”

Section: Nuclear Receptor Activationmentioning

confidence: 89%

“…Both CAR and PXR are involved in a wide range of functions and are known to "crosstalk": they regulate the expression of analogous genes by stimulating similar response elements and show overlapping affinities for some ligands ; Oladimeji et al 2016). Related MOA network describing the relationship between nuclear receptor activation in the liver and liver, thyroid, testis, and pituitary tumors (Elcombe et al 2014;Marty et al 2015;Papineni et al 2015;Peffer et al 2018). CAR: constitutive androstane receptor; PXR: pregnane X receptor; RXR: retinoid X receptor; exp.…”

Section: Nuclear Receptor Activationmentioning

confidence: 99%

Towards a mechanism-based approach for the prediction of nongenotoxic carcinogenic potential of agrochemicals

Heusinkveld

Braakhuis

Gommans

et al. 2020

Critical Reviews in Toxicology

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Chemical substances are subjected to assessment of genotoxic and carcinogenic effects before being marketed to protect man and the environment from health risks. For agrochemicals, the long-term rodent carcinogenicity study is currently required from a regulatory perspective. Although it is the current mainstay for the detection of nongenotoxic carcinogens, carcinogenicity studies are shown to have prominent weaknesses and are subject to ethical and scientific debate. A transition toward a mechanism-based weight-of-evidence approach is considered a requirement to enhance the prediction of carcinogenic potential for environmental (agro)chemicals. The resulting approach should make optimal use of innovative (computational) tools and be less animal demanding. To identify the various mode of actions (MOAs) underlying the nongenotoxic carcinogenic potential of agrochemicals, we conducted an extensive analysis of 411 unique agrochemicals that have been evaluated for carcinogenicity by the United States Environmental Protection Agency (US EPA) and the European Chemicals Agency (ECHA). About one-third of these substances could be categorized as nongenotoxic carcinogens with an average of approximately two tumor types per substance, observed in a variety of organs. For twothird of the tumor cases, an underlying MOA (network) could be identified. This analysis demonstrates that a limited set of MOA (networks) is underlying nongenotoxic carcinogenicity of agrochemicals, illustrating that the transition toward a MOA-driven approach appears manageable. Ultimately the approach should cover relevant MOAs and its associated key events; this will also facilitate the evaluation of the human relevance. This manuscript describes the results of the analysis while identifying knowledge gaps and necessities to achieve a mechanism-based weight-of-evidence approach.

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Mode of action and human relevance of pronamide-induced rat thyroid tumors

Cited by 19 publications

References 28 publications

The effects on the endocrine system under hepatotoxicity induction by phenobarbital and di(2-ethylhexyl)phthalate in intact juvenile male rats

The effects on the endocrine system under hepatotoxicity induction by phenobarbital and di(2-ethylhexyl)phthalate in intact juvenile male rats

Specific alteration of gene expression profile in rats by treatment with thyroid toxicants that inhibit thyroid hormone synthesis

Towards a mechanism-based approach for the prediction of nongenotoxic carcinogenic potential of agrochemicals

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