Assisted reproduction technologies impair placental steroid metabolism

Abstract

The placenta plays a vital role in pregnancy by facilitating steroid passage from maternal to fetal circulation and/or direct production of hormones. Using a murine model, we demonstrated the differences in placental steroid metabolism between pregnancies conceived naturally and with assisted reproduction technologies (ART): in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). While the ovarian steroid production was similar (estrone, 17β-estradiol) or higher (estriol) in ART pregnancies compared to mating, the levels of placental estriol were significantly lower in ART group. Placentas from ART had significantly higher activities of the steroid metabolizing enzymes UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT), which in ICSI were also coupled with decreased activity of the steroid regenerating enzymes β-glucuronidase (β-G) and Aryl sulfatase (AS). Levels of steroid metabolites androstane-3α-17β-diol glucuronide and dehydroepiandrosterone sulfate were higher in fetal compared to maternal blood in ART, but not in mating. This study demonstrates that in murine ART pregnancies, higher metabolism and clearance of steroids by the placenta may seriously affect the passage of essential hormones to the fetus. If a similar phenomenon exists in humans, this could provide a plausible explanation for obstetric and neonatal complications associated with ART, including the higher incidence of low birth weight babies.

Placental profiling of UGT1A enzyme expression and activity and interactions with preeclampsia at term

“…In particular for reproduction, UGT1A1 is known to metabolize estrogenic hormones, thereby terminating estrogen actions and facilitating elimination of the steroid. Our own laboratory has demonstrated assisted reproduction technologies in the mouse model alter steroid glucuronidation at the level of the placenta, in part through transcriptional induction of Ugt1a genes (Collier et al 2009, 2012; Raunig et al 2011). Moreover, we and others have demonstrated that UGT isoform expression is tissue specific and transcription, as well as activities, can be related to levels of sex steroids (Buckley and Klaassen 2007, 2009; Collier et al 2012).…”

“…Hence glucuronidation primarily develops in the postnatal period, independent of gestational age at birth (Burchell et al 1989; Coughtrie et al 1988; Kawade and Onishi 1981; Strassburg et al 2002). Thus, during pregnancy UGT1A isoforms seem to be important for balancing maternal–placental–fetal homeostasis, fetal development and regulating chemicals, nutrients and waste exposure (Collier et al 2004, 2009; Ginsberg and Rice 2009; Raunig et al 2011; Reimers et al 2011). …”

Validation of murine and human placental explant cultures for use in sex steroid and phase II conjugation toxicology studies

“…Arylsulfatase C activity was determined as previously described using the substrate p -nitrophenyl sulfate (Collier et al, 2009; Sugawara et al, 2012). Absorbance was measured at λ = 420 nm for 45 min.…”

Morphologic and molecular changes in the placenta: what we can learn from environmental exposures

“…Several studies have shown that ART increases term placental weight in mice (10–15). Intriguingly, the procedure of transferring blastocyst stage embryos alone can increase overall placental weight, strongly sμggesting that relatively brief procedures can contribute to placental phenotypes (14).…”

“…In human ART placenta, proteome analyses identified genes associated with membrane traffic, metabolism, nucleic acid processing, stress response, and cytoskeletal functions (12). Also, ART placentas have been shown to have significantly higher steroid metabolizing enzyme activity, resulting in a higher clearance capability (10,42). Althoμgh not entirely clear, this may impact hormone signaling and fetal growth.…”