**The E**ff**ects of Early-Onset Pre-Eclampsia on Placental Creatine Metabolism in the Third Trimester**

**Stacey J. Ellery 1,\*, Padma Murthi 1,2, Paul A. Della Gatta 3, Anthony K. May 3, Miranda L. Davies-Tuck 1, Greg M. Kowalski 3, Damien L. Callahan 4, Clinton R. Bruce 3, Euan M. Wallace 1, David W. Walker 5, Hayley Dickinson 1 and Rod J. Snow 3**


Received: 10 December 2019; Accepted: 24 January 2020; Published: 26 January 2020

**Abstract:** Creatine is a metabolite important for cellular energy homeostasis as it provides spatio-temporal adenosine triphosphate (ATP) buffering for cells with fluctuating energy demands. Here, we examined whether placental creatine metabolism was altered in cases of early-onset pre-eclampsia (PE), a condition known to cause placental metabolic dysfunction. We studied third trimester human placentae collected between 27–40 weeks' gestation from women with early-onset PE (*n* = 20) and gestation-matched normotensive control pregnancies (*n* = 20). Placental total creatine and creatine precursor guanidinoacetate (GAA) content were measured. mRNA expression of the creatine synthesizing enzymes arginine:glycine aminotransferase (*GATM*) and guanidinoacetate methyltransferase (*GAMT*), the creatine transporter (*SLC6A8*), and the creatine kinases (mitochondrial *CKMT1A* & cytosolic *BBCK*) was assessed. Placental protein levels of arginine:glycine aminotransferase (AGAT), GAMT, CKMT1A and BBCK were also determined. Key findings; total creatine content of PE placentae was 38% higher than controls (*p* < 0.01). mRNA expression of *GATM* (*p* < 0.001), *GAMT* (*p* < 0.001), *SLC6A8* (*p* = 0.021) and *BBCK* (*p* < 0.001) was also elevated in PE placentae. No differences in GAA content, nor protein levels of AGAT, GAMT, BBCK or CKMT1A were observed between cohorts. Advancing gestation and birth weight were associated with a down-regulation in placental *GATM* mRNA expression, and a reduction in GAA content, in control placentae. These relationships were absent in PE cases. Our results sugges<sup>t</sup> PE placentae may have an ongoing reliance on the creatine kinase circuit for maintenance of cellular energetics with increased total creatine content and transcriptional changes to creatine synthesizing enzymes and the creatine transporter. Understanding the functional consequences of these changes warrants further investigation.

**Keywords:** placental bioenergetics 1; phosphocreatine 2; metabolism 3; obstetrics 4
