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Contaminant and Environmental Influences on Thyroid Hormone Action in Amphibian Metamorphosis.

ABSTRACT: Aquatic and terrestrial environments are increasingly contaminated by anthropogenic sources that include pharmaceuticals, personal care products, and industrial and agricultural chemicals (i. e., pesticides). Many of these substances have the potential to disrupt endocrine function, yet their effect on thyroid hormone (TH) action has garnered relatively little attention. Anuran postembryonic metamorphosis is strictly dependent on TH and perturbation of this process can serve as a sensitive barometer for the detection and mechanistic elucidation of TH disrupting activities of chemical contaminants and their complex mixtures. The ecological threats posed by these contaminants are further exacerbated by changing environmental conditions such as temperature, photoperiod, pond drying, food restriction, and ultraviolet radiation. We review the current knowledge of several chemical and environmental factors that disrupt TH-dependent metamorphosis in amphibian tadpoles as assessed by morphological, thyroid histology, behavioral, and molecular endpoints. Although the molecular mechanisms for TH disruption have yet to be determined for many chemical and environmental factors, several affect TH synthesis, transport or metabolism with subsequent downstream effects. As molecular dysfunction typically precedes phenotypic or histological pathologies, sensitive assays that detect changes in transcript, protein, or metabolite abundance are indispensable for the timely detection of TH disruption. The emergence and application of 'omics techniques-genomics, transcriptomics, proteomics, metabolomics, and epigenomics-on metamorphosing tadpoles are powerful emerging assets for the rapid, proxy assessment of toxicant or environmental damage for all vertebrates including humans. Moreover, these highly informative 'omics techniques will complement morphological, behavioral, and histological assessments, thereby providing a comprehensive understanding of how TH-dependent signal disruption is propagated by environmental contaminants and factors.

SUBMITTER: Thambirajah AA

PROVIDER: S-EPMC6530347 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Contaminant and Environmental Influences on Thyroid Hormone Action in Amphibian Metamorphosis.

Thambirajah Anita A AA Koide Emily M EM Imbery Jacob J JJ Helbing Caren C CC

Frontiers in endocrinology 20190514

Aquatic and terrestrial environments are increasingly contaminated by anthropogenic sources that include pharmaceuticals, personal care products, and industrial and agricultural chemicals (i. e., pesticides). Many of these substances have the potential to disrupt endocrine function, yet their effect on thyroid hormone (TH) action has garnered relatively little attention. Anuran postembryonic metamorphosis is strictly dependent on TH and perturbation of this process can serve as a sensitive barom ...[more]

PMID: 31156547

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Project description:BackgroundChronic exposure to excess arsenic in drinking water has been strongly associated with increased risks of multiple cancers, diabetes, heart disease, and reproductive and developmental problems in humans. We previously demonstrated that As, a potent endocrine disruptor at low, environmentally relevant levels, alters steroid signaling at the level of receptor-mediated gene regulation for all five steroid receptors.ObjectivesThe goal of this study was to determine whether As can also disrupt gene regulation via the retinoic acid (RA) receptor (RAR) and/or the thyroid hormone (TH) receptor (TR) and whether these effects are similar to previously observed effects on steroid regulation.Methods and resultsHuman embryonic NT2 or rat pituitary GH3 cells were treated with 0.01-5 microM sodium arsenite for 24 hr, with or without RA or TH, respectively, to examine effects of As on receptor-mediated gene transcription. At low, noncytotoxic doses, As significantly altered RAR-dependent gene transcription of a transfected RAR response element-luciferase construct and the native RA-inducible cytochrome P450 CYP26A gene in NT2 cells. Likewise, low-dose As significantly altered expression of a transfected TR response element-luciferase construct and the endogenous TR-regulated type I deiodinase (DIO1) gene in a similar manner in GH3 cells. An amphibian ex vivo tail metamorphosis assay was used to examine whether endocrine disruption by low-dose As could have specific pathophysiologic consequences, because tail metamorphosis is tightly controlled by TH through TR. TH-dependent tail shrinkage was inhibited in a dose-dependent manner by 0.1- 4.0 microM As.ConclusionsAs had similar effects on RAR- and TR-mediated gene regulation as those previously observed for the steroid receptors, suggesting a common mechanism or action. Arsenic also profoundly affected a TR-dependent developmental process in a model animal system at very low concentrations. Because RAR and TH are critical for both normal human development and adult function and their dysregulation is associated with many disease processes, disruption of these hormone receptor-dependent processes by As is also potentially relevant to human developmental problems and disease risk.

Project description:BackgroundIncreases in temperature variability associated with climate change have critical implications for the phenology of wildlife across the globe. For example, warmer winter temperatures can induce forward shifts in breeding phenology across taxa ("false springs"), which can put organisms at risk of freezing conditions during reproduction or vulnerable early life stages. As human activities continue to encroach on natural ecosystems, it is also important to consider how breeding phenology interacts with other anthropogenic stressors (e.g., pollutants). Using 14 populations of a widespread amphibian (wood frog; Rana sylvatica), we compared 1) growth; 2) tolerance to a common wetland contaminant (NaCl); and 3) the ability of tadpoles to acclimate to lethal NaCl exposure following sublethal exposure earlier in life. We evaluated these metrics across two breeding seasons (2018 and 2019) and across populations of tadpoles whose parents differed in breeding phenology (earlier- versus later-breeding cohorts). In both years, the earlier-breeding cohorts completed breeding activity prior to a winter storm and later-breeding cohorts completed breeding activities after a winter storm. The freezing conditions that later-breeding cohorts were exposed to in 2018 were more severe in both magnitude and duration than those in 2019.ResultsIn 2018, offspring of the later-breeding cohort were larger but less tolerant of NaCl compared to offspring of the earlier-breeding cohort. The offspring of the earlier-breeding cohort additionally were able to acclimate to a lethal concentration of NaCl following sublethal exposure earlier in life, while the later-breeding cohort became less tolerant of NaCl following acclimation. Interestingly, in 2019, the warmer of the two breeding seasons, we did not detect the negative effects of later breeding phenology on responses to NaCl.ConclusionsThese results suggest that phenological shifts that expose breeding amphibians to freezing conditions can have cascading consequences on offspring mass and ability to tolerate future stressors but likely depends on the severity of the freeze event.

Project description: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 fixed-stage 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. Environ Toxicol Chem 2021;40:2135-2144. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Dataset Information

Contaminant and Environmental Influences on Thyroid Hormone Action in Amphibian Metamorphosis.

Publications

Contaminant and Environmental Influences on Thyroid Hormone Action in Amphibian Metamorphosis.

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