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Photoperiod history-dependent responses to intermediate day lengths engage hypothalamic iodothyronine deiodinase type III mRNA expression.

ABSTRACT: Perihypothalamic thyroid hormone signaling features prominently in the seasonal control of reproductive physiology. Triiodothyronine (T(3)) signaling stimulates gonadal development, and decrements in T(3) signaling are associated with gonadal regression. Type 3 iodothyronine deiodinase (DIO3) converts the prohormone thyroxine (T(4)) into biologically inactive 3,3',5'-triiodothyronine, and in long-day breeding Siberian hamsters exposure to long (LD) and short (SD) photoperiods, respectively, inhibit and stimulate hypothalamic dio3 mRNA expression. Reproductive responses to intermediate-duration photoperiods (IntD) occur in a history-dependent manner; IntDs are interpreted as inhibitory only when preceded by longer photoperiods. Because dio3 expression has only been evaluated under LD or SD photoperiods, it is not known whether hypothalamic dio3 encodes absolute photoperiod duration or the reproductive interpretation of photoperiod. Male Siberian hamsters with and without a prior history of LD were exposed to IntD photoperiods, and hypothalamic dio3 mRNA expression was measured 6 wk later. Hamsters with a LD photoperiod history exhibited gonadal regression in IntD and a marked upregulation of hypothalamic dio3 expression, whereas in hamsters without prior exposure to LD, gonadal responses to IntD were absent, and dio3 expression remained low. Patterns of deiodinase expression in hamsters maintained in chronic IntD photoperiods did not appear to reflect feedback effects of gonadal status. Hypothalamic expression of dio3 does not exclusively reflect ambient photoperiod, but rather the context-dependent reproductive interpretation of photoperiod. Neuroendocrine mechanisms that compare current and prior photoperiods, which permit detection of directional changes in day length, occur either upstream, or at the level, of hypothalamic dio3 expression.

SUBMITTER: Kampf-Lassin A

PROVIDER: S-EPMC3627951 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Photoperiod history-dependent responses to intermediate day lengths engage hypothalamic iodothyronine deiodinase type III mRNA expression.

Kampf-Lassin August A Prendergast Brian J BJ

American journal of physiology. Regulatory, integrative and comparative physiology 20130213 8

Perihypothalamic thyroid hormone signaling features prominently in the seasonal control of reproductive physiology. Triiodothyronine (T(3)) signaling stimulates gonadal development, and decrements in T(3) signaling are associated with gonadal regression. Type 3 iodothyronine deiodinase (DIO3) converts the prohormone thyroxine (T(4)) into biologically inactive 3,3',5'-triiodothyronine, and in long-day breeding Siberian hamsters exposure to long (LD) and short (SD) photoperiods, respectively, inhi ...[more]

PMID: 23408031

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Project description:PurposeThe development of the selective RET inhibitors selpercatinib and pralsetinib has revolutionized the treatment of metastatic progressive RET-mutant medullary thyroid carcinoma (MTC) and other RET-driven cancers, given their more favorable side-effect profile. The aim of this study is to investigate the mechanisms of selpercatinib-induced thyroid dysfunction in athyreotic patients with RET-mutant MTC and in patients with RET-mutant non-small-cell lung cancer (NSCLC) who had a functional thyroid.Materials and methodsThyroid hormone levels were evaluated in an observational cohort of five athyreotic patients with MTC and 30 patients with NSCLC before and after initiation of selpercatinib. In vitro experiments to identify the mechanism of selpercatinib-induced thyroid dysfunction were conducted in cells expressing endogenous D1, D2, and D3 iodothyronine deiodinases.ResultsUpon initiating treatment with selpercatinib, athyreotic patients developed clinical hypothyroidism with approximately 60% lower T3 levels despite adequate levothyroxine supplementation, whereas in patients with NSCLC, who retain a normal thyroid, selpercatinib resulted in a more attenuated reduction in serum T3, which was dose-dependent. We conducted studies in cells endogenously expressing either D1, D2, or D3, the three iodothyronine deiodinases. Selpercatinib inhibited D2-mediated T3 production in MSTO-211 cells by 50%. A modest repression of D2 mRNA was present in human thyroid cancer TT cells that express RET, but not in the MSTO-211 cells that do not. No effect of the drug was observed on D1 (activating deiodinase) or D3 (inactivating deiodinase). Thus, a nontranscriptional effect of selpercatinib on D2 activity is the most plausible explanation for the low T3 levels.ConclusionAn off-target effect of selpercatinib on D2-mediated T3 production leads to clinical hypothyroidism, primarily in levothyroxine-treated athyreotic patients. Liothyronine supplementation was needed to achieve normal T3 levels and restore clinical euthyroidism.

Dataset Information

Photoperiod history-dependent responses to intermediate day lengths engage hypothalamic iodothyronine deiodinase type III mRNA expression.

Publications

Photoperiod history-dependent responses to intermediate day lengths engage hypothalamic iodothyronine deiodinase type III mRNA expression.

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