Identification of thyroid hormone target genes in human cells

Moeller, LC; Dumitrescu, Alexandra M.; Walker, Robert L.; Meltzer, Paul S.; Refetoff, Samuel

doi:10.1055/s-2005-863002

Cited by 3 publications

(2 citation statements)

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Section: Key Event Descriptionmentioning

confidence: 99%

Deiodinase 2 inhibition leading to increased mortality via reduced anterior swim bladder inflation

2022

OECD Series on Adverse Outcome Pathways

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All key events in this AOP are plausibly applicable to both sexes. Sex differences are not often investigated in tests using early life stages of fish. For zebrafish and fathead minnow, it is currently unclear whether sex-related differences are important in determining the magnitude of the changes across the sequence of events in this AOP. Different fish species have different sex determination and differentiation strategies. Zebrafish do not have identifiable heteromorphic sex chromosomes and sex is determined by multiple genes and influenced by the environment . Zebrafish are undifferentiated gonochorists since both sexes initially develop an immature ovary (Maack and Segner, 2003). Immature ovary development progresses until approximately the onset of the third week. Later, in female fish immature ovaries continue to develop further, while male fish undergo transformation of ovaries into testes. Final transformation into testes varies among male individuals, however finishes usually around 6 weeks post fertilization. Since the anterior chamber inflates around 21 days post fertilization in zebrafish, sex differences are expected to play a minor role in the current AOP. Fathead minnow gonad differentiation also occurs during larval development. Fathead minnows utilize a XY sex determination strategy and markers can be used to genotype sex in life stages where the sex is not yet clearly defined morphologically . Ovarian differentiation starts at 10 dph followed by rapid development . At 25 dph germ cells of all stages up to the primary oocytes stage were present and at 120 dph, vitellogenic oocytes were present. The germ cells (spermatogonia) of the developing testes only entered meiosis around 90-120 dph. Mature testes with spermatozoa are present around 150 dph. Since the anterior chamber inflates around 14 days post fertilization (9 dph) in fathead minnows, sex differences are expected to play a minor role in the current AOP. Essentiality of the Key EventsOverall, the confidence in the supporting data for essentiality of KEs within the AOP is moderate. There is evidence from deiodinase knockdowns showing the link with reduced posterior chamber inflation and the essentiality for downstream effects, but anterior chamber inflation was not studied. There is additional indirect evidence that reduced thyroid hormone synthesis causes reduced anterior swim bladder inflation: Chopra et al. (2019) showed that knockdown of dual oxidase, important for thyroid hormone synthesis, reduced anterior swim bladder inflation. It should be noted that dual oxidase also plays a role in oxidative stress. There is also evidence that alleviation of the effect on anterior chamber inflation reduces the effect on swimming performance.

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Section: Key Event Descriptionmentioning

confidence: 99%

Deiodinase 2 inhibition leading to increased mortality via reduced anterior swim bladder inflation

2022

OECD Series on Adverse Outcome Pathways

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“…These thyroid-binding proteins serve as hormonal storage which ensures their even and constant distribution in the different tissues, while they protect the most sensitive ones in the case of severe changes in thyroid availability, like in thyroidectomies (Obregon et al, 1981). Initially, it was believed that all of the effects of TH were mediated by the binding of T3 to the thyroid nuclear receptors (TRa and TRb), a notion which is now questionable due to the increasing evidence that support the non-genomic action of TH (Davis et al, 2010, Moeller et al, 2006. Many non-nuclear TH binding sites have been identified to date and they usually lead to rapid cellular response in TH-effects (Bassett et al, 2003) Four types of thyroid hormone signaling have been defined (Anyetei-Anum et al, 2018): type 1 is the canonical pathway in which liganded TR binds directly to DNA; type 2 describes liganded TR tethered to chromatin-associated proteins, but not bound to DNA directly; type 3 suggests that liganded TR can exert its function without recruitment to chromatin in either the nucleus or cytoplasm; and type 4 proposes that thyroid hormone acts at the plasma membrane or in the cytoplasm without binding TR, a mechanism of action that is emerging as a key component of thyroid hormone signaling.…”

Section: Key Event Descriptionmentioning

confidence: 99%

Deiodinase 2 inhibition leading to increased mortality via reduced posterior swim bladder inflation

2022

OECD Series on Adverse Outcome Pathways

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This AOP describes the sequence of events leading from deiodinase inhibition to increased mortality via reduced posterior swim bladder inflation. Disruption of the thyroid hormone system is increasingly being recognized as an important toxicity pathway that can cause many adverse outcomes, including developmental abnormalities. Three types of iodothyronine deiodinases (DIO1-3) have been described in vertebrates that activate or inactivate THs and are therefore important mediators of thyroid hormone (TH) action. Type II deiodinase (DIO2) has thyroxine (T4) as a preferred substrate and is mostly important for converting T4 to the more biologically active triiodothyronine (T3). Inhibition of DIO2 therefore reduces T3 levels. As in amphibians, the transition between the different developmental phases in fish, including maturation and inflation of the swim bladder, is mediated by THs (Brown et al., 1988;. The swim bladder is a gas-filled organ that typically consists of two chambers (Robertson et al., 2007). The posterior chamber inflates during early development in the embryonic phase, while the anterior chamber inflates during late development in the larval phase. This AOP describes how DIO2 inhibition results in reduced T3 levels, which prohibit normal inflation of the posterior chamber of the swim bladder in the embryonic phase. The posterior chamber is important for regulating buoyancy and thus for swimming performance (Robertson et al., 2007). Reduced swimming performance reduces chances of survival due to a decreased ability to forage and avoid predators. The final adverse outcome is a decrease of the population growth rate. Since many AOPs eventually lead to this more general adverse outcome at the population level, the more specific and informative adverse outcome at the organismal level, increased mortality, is used in the AOP title. Support for this AOP is mainly based on chemical exposures in zebrafish and fathead minnows (

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Effects of Long-Term Thyroid Hormone Level Alterations, n-3 Poly-unsaturated Fatty Acid Supplementation and Statin Administration in Rats

Soukup

2014

Physiol Res

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Thyroid hormones (THs) play multiple roles in the organism and alterations of their levels can result in many pathological changes. Currently, we use hyperthyroid and hypothyroid rats as “models of a diseased organism” and analyze whether n-3 polyunsaturated fatty acids (n-3 PUFA) administration can ameliorate TH-induced pathophysiological changes. We investigate myosin heavy chain composition, calsequestrin levels, changes in cardiac tissue remodeling and cell-to-cell communication, expression of protein kinases, mitochondrial functions, oxidative stress markers and cell death, changes in serum lipid levels, activities of key enzymes of thyroid hormone metabolism, activity of acetylcholine esterase and membrane anisotropy, as well as mobile behavior and thermal sensitivity. Additionally we also mention our pilot experiments dealing with the effect of statin administration on skeletal muscles and sensory functions. As THs and n-3 PUFA possess multiple sites of potential action, we hope that our complex research will contribute to a better understanding of their actions, which can be useful in the treatment of different pathophysiological events including cardiac insufficiency in humans.

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Identification of thyroid hormone target genes in human cells

Cited by 3 publications

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Deiodinase 2 inhibition leading to increased mortality via reduced anterior swim bladder inflation

Deiodinase 2 inhibition leading to increased mortality via reduced anterior swim bladder inflation

Deiodinase 2 inhibition leading to increased mortality via reduced posterior swim bladder inflation

Effects of Long-Term Thyroid Hormone Level Alterations, n-3 Poly-unsaturated Fatty Acid Supplementation and Statin Administration in Rats

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