Effects of single and repetitive valproic acid administration on the gene expression of placental transporters in pregnant rats: An analysis by gestational period

Abstract

The use of valproic acid (VPA), an antiepileptic drug, during pregnancy, is known to increase various fetal risks. Since VPA has been known to inhibit histone deacetylases (HDACs); its administration could alter gene transcription levels. However, in vivo effects of VPA administration on placental transporters have not been fully elucidated. The purpose of the present study was to comprehensively evaluate the effects of single and repetitive VPA administration on the expression of placental transporters and analyze them by gestational day. We investigated 18 transporters ( 8ATP-binding cassette (ABC) and 10 solute carrier (SLC) transporters) in the placentas of pregnant rats that were orally administered 400 mg/kg/day VPA for one or four days, during mid-or late gestation. In the control rats, 4 ABC transporter genes (Abcb1a, 1b, Abcc2, Abcc4) were upregulated, 3 (Abcc3, Abcc5, Abcg2) downregulated through gestation, whereas 1 (Abcc1) was not changed.Regarding SLC transporters, 6 genes (Slc7a5, Slc16a3, Slc22a3, Slc22a4, Slco2b1, Slco4a1) were increased, 1 (Slc29a1) decreased through gestation, whereas 3 (Slc7a8, Slc22a5, Slco2a1) showed no significant change. Single VPA administration altered the expression of 9 transporters and repetitive administration, 13 transporters. In particular, VPA remarkably decreased Abcc4 and Slc22a4 in late gestation and increased Abcc5 during mid-gestation. Our findings indicated that VPA administration changed transporter expression levels in rat placenta, and suggested that sensitivity to VPA differs across gestational stages.

Transcriptomics and Other Omics Approaches to Investigate Effects of Xenobiotics on the Placenta

“…VPA is one of the primary AED prescribed to pregnant women, even though current data suggests that it may be associated with adverse fetal outcomes and behavioral deficits in children exposed in utero to this drug (Eadie, 2014;Elkjaer et al, 2018;Richards et al, 2019;Vajda et al, 2019;Daugaard et al, 2020). The placenta is also not immune to the effects of this AED (Khera, 1992;Meir et al, 2016;Tetro et al, 2019;Jinno et al, 2020;Shafique and Winn, 2021), and VPA-induced changes in the placenta may adversely affect fetal development, including the brain.…”

“…Placental folate concentrations were also decreased with VPA treatment. VPA treatment to pregnant rats altered the expression of other transporter genes with Abcc4 and Slc22a4 reduced in late gestation, but Abcc5 was increased by VPA during mid-gestation (Jinno et al, 2020). Whether such changes on transporter gene expression patterns in the human and rat placenta is due to HDAC inhibition or other biological effects of VPA remains uncertain.…”

Identification of the correlations between interleukin-27 (IL-27) and immune-inflammatory imbalance in preterm birth

“…Strikingly, TIFA induces the HMGB1 secretion from hepatocytes in vitro, while the increase of HMGB1 in the amniotic cavity is one of the predisposing factors for PTB [64][65][66]. In slight contrast to the former two, SLC22A4 encodes an organic cation transporter and plasma integral membrane protein that transports drugs and L-carnitine to the placenta during the gestational period [67,68]. However, as per the previous studies, SLC22A4 gene polymorphism is associated with an increased risk of inflammatory bowel disease and rheumatoid arthritis, and immune imbalance in these diseases is similar to that of PTB [69,70].…”

OCTN1: A Widely Studied but Still Enigmatic Organic Cation Transporter Linked to Human Pathology and Drug Interactions

“…A role of OCTN1 in cancer has been reported [ 104 ]. This relationship has been further explored since, as an acetylcholine transporter, it is considered a component of the non-neuronal cholinergic system (see Section 4.1.3 ); as such, it should be involved in the pathophysiology of lung cancer [ 105 ].…”