Evaluating Iodide Recycling Inhibition as a Novel Molecular Initiating Event for Thyroid Axis Disruption in Amphibians

Olker, Jennifer H.; Haselman, Jonathan T.; Kosian, Patricia A.; Donnay, Kelby G; Korte, Joseph J.; Blanksma, Chad A.; Hornung, Michael W.; Degitz, Sigmund J.

doi:10.1093/toxsci/kfy203

Cited by 11 publications

(12 citation statements)

References 41 publications

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“…These studies use NF stage 62 as the termination stage to align with the LAGDA test guideline, which includes a time to NF stage 62 endpoint in its design. This also addresses potential concerns that terminating at NF stage 58 may not be as sensitive for detecting all thyroid modes of action (Olker et al, 2018). Running the EAMA up to NF stage 62 would incorporate the metamorphic climax, an important developmental milestone.…”

Section: Further Experimental and Statistical Considerationsmentioning

confidence: 99%

“…An alternative fixed-stage test design (EAMA) has been developed to account for some of the above limitations of the fixed-time design of the AMA (US Environmental Protection Agency 2013a; Ortego et al 2014;Haselman et al 2016;Olker et al 2018;Haselman et al 2020). In this alternative design, the experimental set-up, acclimation, initiation, and daily observations are similar to the current AMA guidelines.…”

Section: The Ama and Its Extended Version (Eama)mentioning

confidence: 99%

“…The relevance of the AMA as an indicator of adversity can be enhanced by extending the test duration and adding endpoint measurements at NF stage 62 as in the LAGDA (Figure 1; Table 3). The NF stage 62 encompasses metamorphic climax, and the time to reach NF stage 62 is, therefore, sensitive to modes of action that limit peak thyroid hormone levels in the developing tadpole, especially at later stages of metamorphosis (see Denver 2009; Vitt and Caldwell 2013; Olker et al 2018; Haselman et al 2020). Increasing the number of test concentrations to 4 or 5 (from 3) would improve the resolution of effects, allowing no‐observed‐effect concentration or effect concentration, percentage determinations—not foreseen when the AMA is run as a screening test (Wheeler et al 2014; Organisation for Economic Co‐operation and Development 2018a).…”

Section: Introductionmentioning

confidence: 99%

“…Sodium perchlorate was chosen to enable comparison of the results obtained in the EAMA with those generated in the AMA during the validation effort (Organisation for Economic Co‐operation and Development 2008b ). Although NF stage 58 was chosen as the terminal stage in this demonstration study based on the easily identifiable morphological marker of forelimb emergence (as in Saka and Tada 2021 , using Silurana tropicalis , formerly Xenopus tropicalis ), extending the assay to NF stage 62 would more inclusively cover metamorphic climax and sensitively assess modes of action responsible for limiting peak thyroid hormone levels (Olker et al 2018 ; Haselman et al 2020 ). Assessing stage 62 also aligns the EAMA with the assessment of T‐mediated endpoints in the LAGDA.…”

Section: Introductionmentioning

confidence: 99%

“…Fixed‐stage determination has been commonly used in amphibian development tests (Ankley et al 1998 ; Allran and Karasov 2000 ; Opitz et al 2006 ; Olker et al 2018 ; Haselman et al 2020 ). Using ethylenethiourea as the test substance, Opitz et al ( 2006 ) demonstrated that both the determination of X. laevis developmental stage after a defined exposure period (exposure day 20 in their study) and the monitoring of tadpoles for the time required until forelimb emergence, which characterizes the transition of tadpoles from NF stage 57 to 58, consistently detected developmental delay and even complete inhibition of metamorphosis for concentrations ≥25 mg/L.…”

Section: Introductionmentioning

confidence: 99%

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The Extended Amphibian Metamorphosis Assay: A Thyroid-Specific and Less Animal-Intensive Alternative to the Larval Amphibian Growth and Development Assay

Ortego

Olmstead²,

Weltje³

et al. 2021

Environmental Toxicology and Chemistry

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The amphibian metamorphosis assay (AMA; US Environmental Protection Agency [USEPA] test guideline 890.1100 and Organisation for Economic Co-Operation and Development test guideline 231) has been used for more than a decade to assess the potential thyroid-mediated endocrine activity of chemicals. In 2013, in the context of the Endocrine Disruptor Screening Program of the USEPA, a Scientific Advisory Panel reviewed the results from 18 studies and recommended changes to the AMA test guideline, including a modification to a fixed-stage design rather than a fixed-time (i.e., 21-d) design. We describe an extended test design for the AMA (or EAMA) that includes thyroid histopathology and time to metamorphosis (Nieuwkoop-Faber [NF] stage 62), to address both the issues with the fixed-time design and the specific question of thyroid-mediated adversity in a shorter assay than the larval amphibian growth and development assay (LAGDA; Organisation for Economic Co-Operation and Development test guideline 241), using fewer animals and resources. A demonstration study was conducted with the EAMA (up to NF stage 58) using sodium perchlorate. Data analyses and interpretation of the fixed-stage design of the EAMA are more straightforward than the fixed-time design because the fixedstage design avoids confounded morphometric measurements and thyroid histopathology caused by varying developmental stages at test termination. It also results in greater statistical power to detect metamorphic delays than the fixed-time design. By preferentially extending the AMA to NF stage 62, suitable data can be produced to evaluate thyroid-mediated adversity and preclude the need to perform a LAGDA for thyroid mode of action analysis. The LAGDA remains of further interest should investigations of longer term effects related to sexual development modulated though the hypothalamus-pituitary-gonadal axis be necessary. However, reproduction assessment or life cycle testing is currently not addressed in the LAGDA study design. This is better addressed by higher tier studies in fish, which should then include specific thyroid-related endpoints.

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Section: Further Experimental and Statistical Considerationsmentioning

confidence: 99%

Section: The Ama and Its Extended Version (Eama)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Extended Amphibian Metamorphosis Assay: A Thyroid-Specific and Less Animal-Intensive Alternative to the Larval Amphibian Growth and Development Assay

Ortego

Olmstead²,

Weltje³

et al. 2021

Environmental Toxicology and Chemistry

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Importance of diet in amphibian metamorphosis‐based studies designed to assess the risk of thyroid active substances

Fort

Leopold²,

Wolf

et al. 2022

J of Applied Toxicology

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The present study evaluated the hypothesis that dietary quality used in historical studies may impact the effects of chemical stressors on premetamorphic development and metamorphosis due to suboptimal nutritional quality. A modified Amphibian Metamorphosis Assay (AMA) was performed in which Nieuwkoop and Faber (NF) Stage 47 tadpoles of Xenopus laevis were exposed for 32 days to iodide (I À )deficient FETAX solution supplemented with <0.025, 0.17, 0.52, 1.58, and 4.80 μg I À /L (measured concentrations 0.061, 0.220, 0.614, 1.65, and 4.73 μg I À /L) and fed a pureed Frog Brittle (FB) diet. An AMA guideline benchmark group (four replicates) exposed to dechlorinated tap water and fed standard Sera Micron Nature ® (SMN) diet was evaluated concurrently. Developmental delay, observed as changes in stage distribution or median developmental stage, occurred in FB treatments with 0.061, 0.220, and 0.614 μg/L I À , respectively. Developmental rates and hind limb length of the 1.65 and 4.73 μg/L I À groups were similar to each other, but both treatments fell short of the developmental rate achieved by the SMN benchmark. Iodide supplementation also had no impact on nonthyroidal growth endpoints, which were markedly reduced in FB-fed frogs compared with their SMN-fed counterparts. All larvae that received the FB diet had mildly to severely hypoplastic/atrophic thyroids, a condition for which iodine supplementation had little if any ameliorative effect. Collectively, these results suggested that nutritional deficiencies in the FB diet negatively affected both growth and metamorphic development, the latter of which was only compensated to a limited extent by iodine supplementation.

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Evaluating potential developmental toxicity of perfluoroalkyl and polyfluoroalkyl substances in Xenopus laevis embryos and larvae

Degitz,

Degoey,

Haselman

et al. 2024

J of Applied Toxicology

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As part of the US Environmental Protection Agency's perfluoroalkyl and polyfluoroalkyl substances (PFAS) Action Plan, the agency is committed to increasing our understanding of the potential ecological effects of PFAS. The objective of these studies was to examine the developmental toxicity of PFAS using the laboratory model amphibian species Xenopus laevis. We had two primary aims: (1) to understand the developmental toxicity of a structurally diverse set of PFAS compounds in developing embryos and (2) to characterize the potential impacts of perfluorooctanesulfonic acid (PFOS), perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), and hexafluoropropylene oxide‐dimer acid (HFPO‐DA a.k.a. GenX), on growth and thyroid hormone‐controlled metamorphosis. We employed a combination of static renewal and flow‐through exposure designs. Embryos were exposed to 17 structurally diverse PFAS starting at the midblastula stage through the completion of organogenesis (96 h). To investigate impacts on PFOS, PFOA, PFHxS, and HFPO‐DA on development and metamorphosis, larvae were exposed from premetamorphosis (Nieuwkoop Faber stage 51 or 54) through pro metamorphosis. Of the PFAS tested in embryos, only 1H,1H,10H,10H‐perfluorodecane‐1,10‐diol (FC10‐diol) and perfluorohexanesulfonamide (FHxSA) exposure resulted in clear concentration‐dependent developmental toxicity. For both of these PFAS, a significant increase in mortality was observed at 2.5 and 5 mg/L. For FC10‐diol, 100% of the surviving embryos were malformed at 1.25 and 2.5 mg/L, while for FHxSA, a significant increase in malformations (100%) was observed at 2.5 and 5 mg/L. Developmental stage achieved was the most sensitive endpoint with significant effects observed at 1.25 and 0.625 mg/L for FC10‐diol and FHxSA, respectively. In larval studies, we observed impacts on growth following exposure to PFHxS and PFOS at concentrations of 100 and 2.5 mg/L, respectively, while no impacts were observed in larvae when exposed to PFOA and HFPO‐DA at concentration of 100 mg/L. Further, we did not observe impacts on thyroid endpoints in exposed larvae. These experiments have broadened our understanding of the impact of PFAS on anuran development.

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Evaluating Iodide Recycling Inhibition as a Novel Molecular Initiating Event for Thyroid Axis Disruption in Amphibians

Cited by 11 publications

References 41 publications

The Extended Amphibian Metamorphosis Assay: A Thyroid-Specific and Less Animal-Intensive Alternative to the Larval Amphibian Growth and Development Assay

The Extended Amphibian Metamorphosis Assay: A Thyroid-Specific and Less Animal-Intensive Alternative to the Larval Amphibian Growth and Development Assay

Importance of diet in amphibian metamorphosis‐based studies designed to assess the risk of thyroid active substances

Evaluating potential developmental toxicity of perfluoroalkyl and polyfluoroalkyl substances in Xenopus laevis embryos and larvae

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