Changes in the Endometrial Transcriptome During the Bovine Estrous Cycle: Effect of Low Circulating Progesterone and Consequences for Conceptus Elongation

Abstract

In cattle, elevated concentrations of circulating progesterone (P4) in the immediate postconception period are associated with advanced conceptus development, while low P4 is implicated as a causative factor in low pregnancy rates observed in dairy cows. This study aimed to: 1) describe the transcriptional changes that occur in the bovine endometrium during the estrous cycle, 2) determine how elevated P4 affects these changes, 3) identify if low P4 alters the expression of these genes, and 4) assess the impact that low P4 has on conceptus development. Relatively few differences occurred in endometrial gene expression during the early luteal phase of the estrous cycle (Day 5 vs. 7), but comparison of endometria from more distant stages of the luteal phase (Day 7 vs. 13) revealed large transcriptional changes, which were significantly altered by exogenous supplementation of P4. Induction of low circulating P4 altered the normal temporal changes in gene expression, and these changes were coordinate with a delay in the down-regulation of the PGR from the LE and GE. Altered endometrial gene expression induced by low P4 was associated with a reduced capacity of the uterus to support conceptus development after embryo transfer on Day 7. In conclusion, the present study provides clear evidence that the temporal changes in the transcriptome of the endometrium of cyclic heifers are sensitive to circulating P4 concentrations in the first few days after estrus. Under low P4 conditions, a suboptimal uterine environment with reduced ability to support conceptus elongation is observed.

Physiological and practical effects of progesterone on reproduction in dairy cattle

“…However, it seems clear that there are dramatic differences in endometrial gene expression as the luteal phase progresses and that early supplementation with P4 can induce earlier expression of this P4 program (McNeill et al, 2006;Forde et al, 2009 and. The P4-induced changes in uterine gene expression can have dramatic consequences for the development of the embryos (Forde et al, 2011).…”

“…However, it seems clear that there are dramatic differences in endometrial gene expression as the luteal phase progresses and that early supplementation with P4 can induce earlier expression of this P4 program (McNeill et al, 2006;Forde et al, 2009 and. The P4-induced changes in uterine gene expression can have dramatic consequences for the development of the embryos (Forde et al, 2011).There have been numerous studies that have evaluated the effects of P4 supplementation on fertility in cattle with the earliest experiments conducted in the 1950s (Herrick, 1953;Wiltbank et al, 1956). Throughout the last 60 years (reviewed by Mann and Lamming, 1999), there have been numerous methods to increase P4 including: treatment with exogenous P4 (injectable P4; PRID; or CIDR) or by treatments attempting to ovulate a follicle and produce an accessory CL (human chorionic gonadotropin (hCG); or GnRH).…”

Maternal-embryo interaction leading up to the initiation of implantation of pregnancy in cattle

“…Most convincingly, the embryo does not need to be present in the uterus during the period of P4 elevation in order to benefit from it (Clemente et al, 2009;O'Hara et al, 2014), strongly suggesting that the effect of P4 is via advancing the endometrial transcriptome (Forde et al, 2009) resulting in advancing conceptus elongation (Carter et al, 2008;Clemente et al, 2009). In addition reducing the output of P4 from the CL results in a delay in the temporal changes in the endometrial transcriptome resulting in delayed conceptus elongation in vivo (Forde et al, 2011a and2012a).…”

“…First, supplementation with exogenous P4 advances the down-regulation of the PGR (Okumu et al, 2010) while delaying the output of P4 from the CL, delays the down-regulation of the PGR (Forde et al, 2011a). This has consequences for the expression of genes that contribute to the histotroph; elevating P4 advances or increases the expression of genes while low P4 delays or decreases the expression of genes known to be important for histotroph composition including ANPEP, APOA1, DGAT2, FABP3, IGFBP1, IHH, LCAT, LPL, LTF, MEP1B, NID2, NMN, NPNT, NXPH3, PENK, PLIN2, PRSS23, RBP4, SCG5, SERPINA14, TINGAL1 and TFF3 (Costello et al, 2010;Forde et al, 2011a and2012a;Mullen et al, 2012). The P4 modification of the expression of these genes, and in some cases their protein products, results in a change in the capacity of the uterus to support conceptus elongation.…”

Efeito do ambiente endócrino periovulatório na expressão gênica do endométrio durante a primeira semana do ciclo estral em bovinos: biossíntese e sinalização de eicosanoides

“…Além disso, foram elucidados efeitos benéficos da progesterona no desenvolvimento embrionário durante o início do diestro em experimentos utilizando P4 exógena (CARTER et al, 2008). Forde et al (2011), também evidenciaram os efeitos positivos da progesterona no desenvolvimento de embriões bovinos no dia 7 do ciclo estral (FORDE, et al, 2011 , 2013). Legenda: Via de síntese, sinalização e metabolismo de eicosanoides: a enzima fosfolipase A2 (PLA2) libera o ácido araquidônico (AA) da membrana fosfolipídica e este pode ser convertido a prostanoides pelas cicloxigenase 1 e 2 (PTGS1 e PTGS2) à PGH2 que é o precursor de todos os prostanóides.…”