Thyroid Histopathology Assessments for the Amphibian Metamorphosis Assay to Detect Thyroid-active Substances

Grim, K. Christiana; Wolfe, Marilyn J.; Braunbeck, Thomas; Iguchi, Taisen; Ohta, Yasuhiko; Tooi, Osamu; Touart, Les; Wolf, Douglas C.; Tietge, Joe

doi:10.1177/0192623309335063

Cited by 101 publications

(106 citation statements)

References 7 publications

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“…In addition, in support of the OECD AMA test guideline, a document was developed that provides a standardized approach for evaluating the histology/histopathology of thyroid glands 63 , including an atlas of the normal architecture of amphibian thyroid glands over the course of metamorphosis.…”

Section: Guideline Establishmentmentioning

confidence: 99%

“…Depletion of colloid stores and increases in epithelial cell height are known to occur at climax stages during normal development when TSH synthesis and release by the pituitary and T4 synthesis and secretion by the thyroid gland reach maximum levels 63 . Therefore, there may be difficulty in distinguishing whether histological changes occur in response to alterations of the HPT axis or alternatively merely reflect advanced stages in tadpoles.…”

Section: The Importance and Difficulty Of Histopathological Examinationmentioning

confidence: 99%

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Thyroid Hormone-disrupting Effects and the Amphibian Metamorphosis Assay

2012

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There are continued concerns about endocrine-disrupting chemical effects, and appropriate vertebrate models for assessment of risk are a high priority. Frog tadpoles are very sensitive to environmental substances because of their habitat and the complex processes of metamorphosis regulated by the endocrine system, mainly thyroid hormones. During metamorphosis, marked alteration in hormonal factors occurs, as well as dramatic structural and functional changes in larval tissues. There are a variety of mechanisms determining thyroid hormone balance or disruption directly or indirectly. Direct-acting agents can cause changes in thyroxine synthesis and/or secretion in thyroid through effects on peroxidases, thyroidal iodide uptake, deiodinase, and proteolysis. At the same time, indirect action may result from biochemical processes such as sulfation, deiodination and glucuronidation. Because their potential to disrupt thyroid hormones has been identified as an important consideration for the regulation of chemicals, the OECD and the EPA have each established guidelines that make use of larval African clawed frogs (Xenopus laevis) and frog metamorphosis for screening and testing of potential endocrine disrupters. The guidelines are based on evaluation of alteration in the hypothalamic-pituitary-thyroid axis. One of the primary endpoints is thyroid gland histopathology. Others are mortality, developmental stage, hind limb length, snout-vent length and wet body weight. Regarding histopathological features, the guidelines include core criteria and additional qualitative parameters along with grading. Taking into account the difficulties in evaluating amphibian thyroid glands, which change continuously throughout metamorphosis, histopathological examination has been shown to be a very sensitive approach.

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Section: Guideline Establishmentmentioning

confidence: 99%

Section: The Importance and Difficulty Of Histopathological Examinationmentioning

confidence: 99%

Thyroid Hormone-disrupting Effects and the Amphibian Metamorphosis Assay

2012

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“…Based on the recommendations of Grim et al [22], and the descriptions of severity grading in the OECD guidance document [23], thyroid gland hypertrophy and atrophy were graded relative to the control thyroid glands as follows: grade 0 (unremarkable) ¼ less than 20% enlargement or reduction in size compared with controls, grade 1 (mild) ¼ diffuse enlargement or reduction in size up to 50% of the controls, grade 2 (moderate) ¼ diffuse enlargement or reduction in size up to 80% of the control, and grade 3 (severe) ¼ diffuse enlargement or reduction in size greater than 80% of the control. This general scheme was also applied to grade overall amounts of colloid in the gland.…”

Section: Thyroid and Gonad Histopathologymentioning

confidence: 99%

“…The increased height of these follicular cells likely was due to the accelerated metamorphosis (median NF stage ¼ 62), resulting in an advanced stage of development of the thyroid gland in tadpoles exposed to 2.73 mg/L L-thyroxine as compared with the controls (median NF stage ¼ 57). It has been recently reported that the maximal cell height is achieved between NF stages 62 and 63 [22]; therefore, these follicular cells were not considered hypertrophic. Tadpoles exposed to 0.44 mg/L L-thyroxine also exhibited mild to moderate or occasionally severe thyroid glandular atrophy, albeit at a much lower incidence (Table 4).…”

Section: L-thyroxine Exposurementioning

confidence: 99%

Evaluation of the amphibian metamorphosis assay: Exposure to the goitrogen methimazole and the endogenous thyroid hormone L‐thyroxine

Coady

Marino

Thomas

et al. 2010

Enviro Toxic and Chemistry

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The U.S. Environmental Protection Agency (U.S. EPA) has included an amphibian metamorphosis assay (AMA) to detect thyroid active chemicals in Tier 1 testing of their endocrine screening program. To understand the variability, specificity, and reliability of the key endpoints of this assay, two exposure studies with Xenopus laevis tadpoles were conducted with two known thyroid-active compounds, namely, methimazole or L-thyroxine, for a total of 21 d. In addition, various increased-flow-rate treatments were included in the exposures to evaluate the effects of physical stress on metamorphic development. The endpoints examined in the exposures were wet weight, snout-vent length, hind-limb length, developmental stage, and thyroid and gonadal histopathology. As expected, the results indicated that both methimazole and L-thyroxine were thyroid active in the AMA, hind-limb length and thyroid histopathology being the most sensitive endpoints of thyroid activity. Tadpoles that were exposed to the various physical stressors in these experiments showed no signs of altered metamorphic development, and exposure to the thyroid-active compounds had no effect on the developing gonad of X. laevis. Taken together, these results support the use of the AMA as a Tier 1 endocrine screen for detection of potential thyroid pathway activity; however, the lack of a true negative response (no-effect) during the validation process prevents a full evaluation of this assay's specificity at this time.

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“…A comparison of amphibian and mammalian models for detecting thyroid disruption found good concordance in that both detected the majority of 32 environmental chemicals (Pickford 2010). An advantage of the assays using X. laevis, when compared with mammals, is that effects on thyroid disruption can be observed via distinct, relatively specific changes in development (i.e., metamorphosis) as opposed to the more subtle changes in humans and other mammals, such as behavioral and neural developmental effects requiring extensive resources to assess (Grim et al 2009; Nieuwkoop and Faber 1994). An additional advantage of the amphibian model is that there is no serum protein sink/buffer to bind TH as is found in rodents to complicate the toxicokinetics of TH responses.…”

Section: Use Of Alternative Species and In Vitro Assays In An Aop Framentioning

confidence: 99%

Current Perspectives on the Use of Alternative Species in Human Health and Ecological Hazard Assessments

Perkins

Ankley

Crofton

et al. 2013

Environ Health Perspect

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Background: Traditional animal toxicity tests can be time and resource intensive, thereby limiting the number of chemicals that can be comprehensively tested for potential hazards to humans and/or to the environment.Objective: We compared several types of data to demonstrate how alternative models can be used to inform both human and ecological risk assessment.Methods: We reviewed and compared data derived from high throughput in vitro assays to fish reproductive tests for seven chemicals. We investigated whether human-focused assays can be predictive of chemical hazards in the environment. We examined how conserved pathways enable the use of nonmammalian models, such as fathead minnow, zebrafish, and Xenopus laevis, to understand modes of action and to screen for chemical risks to humans.Results: We examined how dose-dependent responses of zebrafish embryos exposed to flusilazole can be extrapolated, using pathway point of departure data and reverse toxicokinetics, to obtain human oral dose hazard values that are similar to published mammalian chronic toxicity values for the chemical. We also examined how development/safety data for human health can be used to help assess potential risks of pharmaceuticals to nontarget species in the environment.Discussion: Using several examples, we demonstrate that pathway-based analysis of chemical effects provides new opportunities to use alternative models (nonmammalian species, in vitro tests) to support decision making while reducing animal use and associated costs.Conclusions: These analyses and examples demonstrate how alternative models can be used to reduce cost and animal use while being protective of both human and ecological health.Citation: Perkins EJ, Ankley GT, Crofton KM, Garcia-Reyero N, LaLone CA, Johnson MS, Tietge JE, Villeneuve DL. 2013. Current perspectives on the use of alternative species in human health and ecological hazard assessments. Environ Health Perspect 121:1002–1010; http://dx.doi.org/10.1289/ehp.1306638

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Thyroid Histopathology Assessments for the Amphibian Metamorphosis Assay to Detect Thyroid-active Substances

Cited by 101 publications

References 7 publications

Thyroid Hormone-disrupting Effects and the Amphibian Metamorphosis Assay

Thyroid Hormone-disrupting Effects and the Amphibian Metamorphosis Assay

Evaluation of the amphibian metamorphosis assay: Exposure to the goitrogen methimazole and the endogenous thyroid hormone L‐thyroxine

Current Perspectives on the Use of Alternative Species in Human Health and Ecological Hazard Assessments

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