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Thyroid Hormone Production and Transplacental Transfer in the “Mother–Fetus” System during Gestational Hyperhomocysteinemia

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Abstract—Accumulation of the amino acid homocysteine in the mother’s body, known as hyperhomocysteinemia, is observed when there is an unbalanced diet during pregnancy, a lack of some vitamins, and genetic defects in methionine cycle enzymes. This increases the risk of microthrombosis in the placenta and developmental delay of brain tissue, neuronal death, and gliosis, leading to impaired cognitive functions in the offspring. A study of the thyroid-dependent system of fetal brain development regulation during chronic prenatal hyperhomocysteinemia induced by a dosed methionine load in female rats was carried out. Thyroxine and triiodothyronine levels in the blood of pregnant females, the content of their transporter transthyretin, expression of receptors (TR-α, TR-β), transmembrane transporters (Oatp1c1, Mct8) and deiodinases (Dio2, Dio3) in the tissue of the placenta and fetal brain were analyzed. A negative effect of hyperhomocysteinemia on Dio3, Oatp1c1 and Mct8 expression in the fetal nervous tissue on E14, as well as a decrease in TR-α expression and an increase in Dio3 in the placenta at the end of pregnancy, were found despite the absence of noticeable disturbances in the thyroid hormone supply to the fetus from the mother. This effect of a high homocysteine level on the functional state of the placenta and on the sensitivity of the developing brain of the offspring to the trophic action of thyroid hormones may be the cause of the developmental delay of fetal nervous tissue.

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ACKNOWLEDGMENTS

The authors express their gratitude to A.O. Shpakov and K.V. Derkach for valuable recommendations and a productive discussion on the functioning of the thyroid signaling axis in rats in normal and pathological ontogenetic development. The authors are grateful to the Center for the Collective Use of Scientific Equipment for Physiological, Biochemical, and Molecular Biological Research (CCU) of the Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences.

Funding

The work was supported by the Russian Foundation for Basic Research grant (20-015-00388) and the State Assignment (075-00408-21-00 and 1021062812133-0-3.2.2).

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  1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia

    A. D. Shcherbitskaia, A. A. Kovalenko & D. S. Vasilev

  2. Ott Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, Russia

    A. D. Shcherbitskaia & Yu. P. Milyutina

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  1. A. D. Shcherbitskaia
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Ethical approval. All animal experiments were performed in accordance with the recommendations of the Declaration of Helsinki and approved by the ethics committees of the Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences (protocol no. 3/2020 of March 18, 2020) and the Ott Institute of Obstetrics, Gynecology, and Reproductive medicine (protocol no. 88 of 12/08/2017).

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Shcherbitskaia, A.D., Kovalenko, A.A., Milyutina, Y.P. et al. Thyroid Hormone Production and Transplacental Transfer in the “Mother–Fetus” System during Gestational Hyperhomocysteinemia. Neurochem. J. 16, 249–262 (2022). https://doi.org/10.1134/S1819712422030102

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