Epigenetic Consequences of in Utero Exposure to Rosuvastatin: Alteration of Histone Methylation Patterns in Newborn Rat Brains.

Karolina Dulka,Melinda Szabo,Zsófia Hoyk,István Belecz,Noémi Lajkó,Karoly Gulya

doi:10.3390/ijms22073412

Abstract

Rosuvastatin (RST) is primarily used to treat high cholesterol levels. As it has potentially harmful but not well-documented effects on embryos, RST is contraindicated during pregnancy. To demonstrate whether RST could induce molecular epigenetic events in the brains of newborn rats, pregnant mothers were treated daily with oral RST from the 11th day of pregnancy for 10 days (or until delivery). On postnatal day 1, the brains of the control and RST-treated rats were removed for Western blot or immunohistochemical analyses. Several antibodies that recognize different methylation sites for H2A, H2B, H3, and H4 histones were quantified. Analyses of cell-type-specific markers in the newborn brains demonstrated that prenatal RST administration did not affect the composition and cell type ratios as compared to the controls. Prenatal RST administration did, however, induce a general, nonsignificant increase in H2AK118me1, H2BK5me1, H3, H3K9me3, H3K27me3, H3K36me2, H4, H4K20me2, and H4K20me3 levels, compared to the controls. Moreover, significant changes were detected in the number of H3K4me1 and H3K4me3 sites (134.3% ± 19.2% and 127.8% ± 8.5% of the controls, respectively), which are generally recognized as transcriptional activators. Fluorescent/confocal immunohistochemistry for cell-type-specific markers and histone methylation marks on tissue sections indicated that most of the increase at these sites belonged to neuronal cell nuclei. Thus, prenatal RST treatment induces epigenetic changes that could affect neuronal differentiation and development.

Highlights

Statins (3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors) are a class of lipid-lowering agents used in the treatment of high cholesterol levels [1]
As recent studies have emphasized the importance of maternal effects on chromatin structure and the interrelationship between the genome, epigenome, and environment [35,36], our aim was to investigate whether RST elicited molecular epigenetic events such as histone methylation in the brains of the newborn rats whose mothers had been treated chronically with the drug
HMG-CoA reductase activity is required for normal placental development in mammals. The inhibition of this enzyme by statins may disrupt membrane synthesis, cellular proliferation and growth, and metabolism and protein glycosylation, which are crucial for the the beneficial effects of statins are well documented [1], there are some circumstances, including pregnancy, in which their use requires caution. The inhibition of this enzyme by statins may disrupt membrane synthesis, cellular proliferation and growth, and metabolism and protein glycosylation, which are crucial for the normal development of the placenta [17]

Summary

Introduction

Statins (3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors) are a class of lipid-lowering agents used in the treatment of high cholesterol levels [1]. Apart from the inhibition of cholesterol synthesis, reduction of levels of low-density lipoproteins and triglycerides, and stimulation of the expression of high-density lipoproteins, they strongly modulate the inflammatory cells surrounding atherosclerotic plaques [2,3]. Statins have long been known to induce apoptosis in various cancer cell lines [10,11], and are associated with antitumor properties [12,13]. Besides their beneficial properties, statins have numerous adverse effects [14]. As a result of their potentially harmful, but not well documented effects on the embryo, it is recommended that statin treatment be discontinued three months before attempting to become pregnant and that statins should not be used during pregnancy or breastfeeding [15]

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