Placental Transport of Amino Acids in Rats with Methionine-Induced Hyperhomocysteinemia

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Yulia P. Milyutina^1,a*, Gleb O. Kerkeshko¹, Dmitrii S. Vasilev^1,2, Irina V. Zalozniaia¹, Sergey K. Bochkovskii¹, Natalia L. Tumanova², Anastasiia D. Shcherbitskaia¹, Anastasiia V. Mikhel¹, Gulrukhsor H. Tolibova¹, Alexander V. Arutjunyan¹

¹D. O. Ott Research Institute of Obstetrics, Gynecology, and Reproductive Medicine, 199034 St. Petersburg, Russia

²I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 St. Petersburg, Russia

^* To whom correspondence should be addressed.

Received: December 2, 2023; Revised: April 11, 2024; Accepted: May 2, 2024

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Maternal hyperhomocysteinemia (HHcy) is a risk factor for intrauterine growth restriction presumably caused by a decrease in the placental transport of nutrients. We investigated the effect of experimental HHcy induced by daily methionine administration to pregnant rats on the free amino acid levels in the maternal and fetal blood, as well as on morphological and biochemical parameters associated with the amino acid transport through the placenta. HHcy caused an increase in the levels of most free amino acids in the maternal blood on gestational day 20, while the levels of some amino acids in the fetal blood were decreased. In rats with HHcy, the maternal sinusoids in the placental labyrinth were narrowed, which was accompanied by aggregation of red blood cells. We also observed an increase in the neutral amino acid transporters (LAT1, SNAT2) protein levels and activation of 4E-BP1, a downstream effector of mTORC1 complex, in the labyrinth zone. Maternal HHcy affected the placental barrier permeability, as evidenced by intensification of the mother-to-fetus transfer of Evans Blue dye. The imbalance in the free amino acid levels in the maternal and fetal blood in HHcy may be due to the competition of homocysteine with other amino acids for common transporters, as well as a decrease in the area of exchange zone between maternal and fetal circulations in the placental labyrinth. Upregulation of the neutral amino acid transporter expression in the labyrinth zone may be a compensatory response to an insufficient intrauterine amino acid supply and fetal growth restriction.

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KEY WORDS: maternal hyperhomocysteinemia, placenta, placental transport, placental barrier, amino acids, mTOR, amino acid transporters

DOI: 10.1134/S0006297924100055

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