Catechol-O-methyltransferase and Pregnancy Outcome: an Appraisal in Rat
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MATERNAL FETAL MEDICINE/BIOLOGY: ORIGINAL ARTICLE
Catechol-O-methyltransferase and Pregnancy Outcome: an Appraisal in Rat Khursheed Iqbal 1,2
&
Pramod Dhakal 1,2,3 & Stephen H. Pierce 1,2 & Michael J. Soares 1,2,4,5,6
Received: 9 June 2020 / Accepted: 5 October 2020 # Society for Reproductive Investigation 2020
Abstract Catechol-O-methyltransferase (COMT) has been shown to be a key regulator of pregnancy outcomes in mouse, and its deficiency is causative in the development of a preeclampsia-like disease process. Preeclampsia is a human pregnancy disorder associated with failure of intrauterine trophoblast cell invasion and trophoblast-guided uterine spiral artery remodeling, which are not welldeveloped in mouse. The purpose of this study was to investigate COMT in rat, a species with deep intrauterine trophoblast invasion. To accomplish this task, we used clustered regularly interspaced short palindromic repeats/Cas9-mediated genome editing of the rat Comt gene. A Comt null rat model was established and its fertility characterized. Comt null male and female rats were viable and fertile. COMT deficiency did not significantly impact pregnancy outcomes, including litter size, placental and fetal weights, Mendelian and sex ratios, or pregnancy-dependent adaptations to hypoxia. Collectively, our findings indicate that pregnancy-associated phenotypic outcomes of COMT deficiency are not equivalent in mouse and rat. In rat, COMT is not required for a successful pregnancy outcome. Keywords COMT . Rat genome editing . Placenta . Pregnancy
Introduction Catechol-O-methyltransferase (COMT) is an enzyme involved in the catabolism of catecholamines and other molecules possessing a catechol structure, including estrogens. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s43032-020-00348-7) contains supplementary material, which is available to authorized users. * Khursheed Iqbal [email protected] 1
Institute for Reproduction and Perinatal Research, University of Kansas Medical Center, Kansas, USA
2
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas, USA
3
Present address: Department of Animal Sciences, University of Missouri, Columbia, MO, USA
4
Department of Pediatrics, University of Kansas Medical Center, Kansas, USA
5
Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas, USA
6
Center for Perinatal Research, Children’s Mercy Research Institute, Children’s Mercy, Kansas, MO, USA
COMT catalyzes the transfer of a methyl group from Sadenosyl-L-methionine (SAM) to a hydroxyl group of catechol-like compounds [1–5]. The COMT gene is highly conserved across species. COMT modifies 2hydroxyestradiol to 2-methoxyestradiol (2ME) [4, 5], a compound with biological functions implicated in regulatory processes associated with pregnancy and placentation [6]. COMT and 2ME have been demonstrated to contribute to the regulation of angiogenesis, trophoblast development, and adaptations to hypoxia [7–12]. Deficits in
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