Progesterone Receptor (PGR) gene polymorphism is associated with susceptibility to preterm birth

Langmia, Immaculate Mbongo; Apalasamy, Yamunah Devi; Omar, Siti Zawaih; Mohamed, Zahurin

doi:10.1186/s12881-015-0202-1

Cited by 16 publications

(10 citation statements)

References 22 publications

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“…correspond to genes previously linked to PTB [66][67][68][69]. Ingenuity Pathway Analysis further identified Esr1 as one of the top upstream regulators impacted in the placental tissues following paternal developmental TCDD exposure (Table 1).…”

Section: Discussionmentioning

confidence: 89%

Paternal developmental toxicant exposure is associated with epigenetic modulation of sperm and placentalPgrandIgf2in a mouse model†

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Mokshagundam

Rinaudo

et al. 2018

Biology of Reproduction

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Preterm birth (PTB), parturition prior to 37 weeks' gestation, is the leading cause of neonatal mortality. The causes of spontaneous PTB are poorly understood; however, recent studies suggest that this condition may arise as a consequence of the parental fetal environment. Specifically, we previously demonstrated that developmental exposure of male mice (F1 animals) to the environmental endocrine disruptor 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was associated with reduced sperm quantity/quality in adulthood and control female partners frequently delivered preterm. Reproductive defects persisted in the F2 and F3 descendants, and spontaneous PTB was common. Reproductive changes in the F3 males, the first generation without direct TCDD exposure, suggest the occurrence of epigenetic alterations in the sperm, which have the potential to impact placental development. Herein, we conducted an epigenetic microarray analysis of control and F1 male-derived placentae, which identified 2171 differentially methylated regions, including the progesterone receptor (Pgr) and insulin-like growth factor (Igf2). To assess if Pgr and Igf2 DNA methylation changes were present in sperm and persist in future generations, we assessed methylation and expression of these genes in F1/F3 sperm and F3-derived placentae. Although alterations in methylation and gene expression were observed, in most tissues, only Pgr reached statistical significance. Despite the modest gene expression changes in Igf2, offspring of F1 and F3 males consistently exhibited IUGR. Taken together, our data indicate that paternal developmental TCDD exposure is associated with transgenerational placental dysfunction, suggesting epigenetic modifications within the sperm have occurred. An evaluation of additional genes and alternative epigenetic mechanisms is warranted.

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Section: Discussionmentioning

confidence: 89%

Paternal developmental toxicant exposure is associated with epigenetic modulation of sperm and placentalPgrandIgf2in a mouse model†

Ding

Mokshagundam

Rinaudo

et al. 2018

Biology of Reproduction

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“…This has been supported by both animal and human studies that have used abortifacient regimens, either by (i) inducing a decline in systemic P4 levels, (ii) corpus luteum lysis or oophorectomy, or (iii) directly antagonizing the effects of P4 by the administration of an anti-progestin such as mifepristone (RU486) (17–22). It has been strongly suggested that the ability of RU486 to promote abortions and labor demonstrates such uterine processes are driven by “functional P4 withdrawal” in humans, which is mediated by altering the expression levels of P4 receptor (PR) isoforms and PR gene polymorphisms in reproductive tissues (23–25). In the immune system, indirect evidence of reduced P4 action at parturition is provided by studies that show a decrease in a lymphocyte-derived downstream immunomodulatory protein known as P4-induced-blocking factor (PIBF) (23, 26–28).…”

Section: Introductionmentioning

confidence: 99%

Progesterone-Related Immune Modulation of Pregnancy and Labor

et al. 2019

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Pregnancy involves a complex interplay between maternal neuroendocrine and immunological systems in order to establish and sustain a growing fetus. It is thought that the uterus at pregnancy transitions from quiescent to laboring state in response to interactions between maternal and fetal systems at least partly via altered neuroendocrine signaling. Progesterone (P4) is a vital hormone in maternal reproductive tissues and immune cells during pregnancy. As such, P4 is widely used in clinical interventions to improve the chance of embryo implantation, as well as reduce the risk of miscarriage and premature labor. Here we review research to date that focus on the pathways through which P4 mediates its actions on both the maternal reproductive and immune system. We will dissect the role of P4 as a modulator of inflammation, both systemic and intrinsic to the uterus, during human pregnancy and labor.

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“…Therefore, mutations interfering with PGR function are associated with an elevated risk of preterm birth (PTB), as well as of breast (MIM: 114480) and ovarian (MIM: 167000) cancers. [12][13][14][15][16][17] PGR arose early in the vertebrate lineage, resulting from multiple rounds of expansions from an ancestral estrogen receptor. 18 Its early origin indicates conserved mechanism(s) underlying female reproduction in vertebrates.…”

Section: Introductionmentioning

confidence: 99%

Natural Selection Has Differentiated the Progesterone Receptor among Human Populations

Hong

Mesiano

et al. 2018

The American Journal of Human Genetics

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The progesterone receptor (PGR) plays a central role in maintaining pregnancy and is significantly associated with medical conditions such as preterm birth that affects 12.6% of all the births in U.S. PGR has been evolving rapidly since the common ancestor of human and chimpanzee, and we herein investigated evolutionary dynamics of PGR during recent human migration and population differentiation. Our study revealed substantial population differentiation at the PGR locus driven by natural selection, where very recent positive selection in East Asians has substantially decreased its genetic diversity by nearly fixing evolutionarily novel alleles. On the contrary, in European populations, the PGR locus has been promoted to a highly polymorphic state likely due to balancing selection. Integrating transcriptome data across multiple tissue types together with large-scale genome-wide association data for preterm birth, our study demonstrated the consequence of the selection event in East Asians on remodeling PGR expression specifically in the ovary and determined a significant association of early spontaneous preterm birth with the evolutionarily selected variants. To reconstruct its evolutionary trajectory on the human lineage, we observed substantial differentiation between modern and archaic humans at the PGR locus, including fixation of a deleterious missense allele in the Neanderthal genome that was later introgressed in modern human populations. Taken together, our study revealed substantial evolutionary innovation in PGR even during very recent human evolution, and its different forms among human populations likely result in differential susceptibility to progesterone-associated disease conditions including preterm birth.

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Progesterone Receptor (PGR) gene polymorphism is associated with susceptibility to preterm birth

Cited by 16 publications

References 22 publications

Paternal developmental toxicant exposure is associated with epigenetic modulation of sperm and placentalPgrandIgf2in a mouse model†

Paternal developmental toxicant exposure is associated with epigenetic modulation of sperm and placentalPgrandIgf2in a mouse model†

Progesterone-Related Immune Modulation of Pregnancy and Labor

Natural Selection Has Differentiated the Progesterone Receptor among Human Populations

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