Thomson P and Langlois VS (2018), Developmental profiles of progesterone receptor...

XB-ART-54944

Gen Comp Endocrinol 2018 Sep 01;265:4-14. doi: 10.1016/j.ygcen.2018.05.017.

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Developmental profiles of progesterone receptor transcripts and molecular responses to gestagen exposure during Silurana tropicalis early development.

Thomson P , Langlois VS .

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Environmental gestagens are an emerging class of contaminants that have been recently measured in surface water and can interfere with reproduction in aquatic vertebrates. Gestagens include endogenous progestogens, such as progesterone (P4), which bind P4-receptors and have critically important roles in vertebrate physiology and reproduction. Gestagens also include synthetic progestins, which are components of human and veterinary drugs, such as melengestrol acetate (MGA). Endogenous progestogens are essential in the regulation of reproduction in mammalian species, but the role of P4 in amphibian larval development remains unclear. This project aims to understand the roles and the regulatory mechanisms of P4 in amphibians and to assess the consequences of exposures to environmental gestagens on the P4-receptor signaling pathways in frogs. Here, we established the developmental profiles of the P4 receptors: the intracellular progesterone receptor (ipgr), the membrane progesterone receptor β (mpgrβ), and the progesterone receptor membrane component 1 (pgrmc1) in Western clawed frog (Silurana tropicalis) embryos using real-time qPCR. P4-receptor mRNAs were detected throughout embryogenesis. Transcripts for ipgr and pgrmc1 were detected in embryos at Nieuwkoop and Faber (NF) stage 2 and 7, indicative of maternal transfer of mRNA. We also assessed the effects of P4 and MGA exposure in embryonic and early larval development. Endocrine responses were evaluated through transcript analysis of a suite of gene targets of interest, including: ipgr, mpgrβ, pgrmc1, androgen receptor (ar), estrogen receptor α (erα), follicle stimulating hormone β (fshβ), prolactin (prl), and the steroid 5-alpha reductase family (srd5α1, 2, and 3). Acute exposure (NF 12-46) to P4 caused a 2- to 5-fold change increase of ipgr, mpgrβ, pgrmc1, and ar mRNA levels at the environmentally relevant concentration of 195 ng/L P4. Acute exposure to MGA induced a 56% decrease of srd5α3 at 1140 ng/L MGA. We conclude that environmental exposure to P4 induced multiple endocrine-related transcript responses in amphibians; however, the differential responses of MGA suggest that the effects of MGA are not mediated through the classical P4 signaling pathway in S. tropicalis.

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Species referenced: Xenopus
Genes referenced: ar fshb mga paqr8 pgr pgrmc1 prl.1 srd5a1 srd5a2 srd5a3

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	Graphical abstract
	Fig. 1. Structural formulas of progesterone (P4; A) and melengestrol acetate (MGA; B).
	Fig. 2. Developmental profiles of the expression of ipgr (A), pgrmc1 (B), and mpgrβ (C) during Silurana tropicalis embryogenesis. Transcript levels were measured in 5–8 replicates of 10 pooled whole embryos and larvae from Nieuwkoop and Faber (NF) 2 (two-cell stage) to NF 46 (beginning of feeding). Data are expressed relative to NF 2 or NF 16, normalized to RNA content. Bars represent the mean + SEM. Data were analyzed using one-way ANOVAs (n = 5–8 per treatment; p < 0.05). Different letters indicate statistically significant differences between stages. The scales of the y-axes vary between graphs. C: water control, SC: solvent control (0.05% EtOH), ipgr: intracellular progesterone receptor, mpgrβ: membrane progesterone receptor beta, pgrmc1: progesterone receptor membrane component 1.
	Fig. 3. Effects of progesterone (P4) on ipgr (A), mpgrβ (B), and pgrmc1 (C), srd5α1 (D), srd5α2 (E), and srd5α3 (F), ar (G) mRNA expression in Silurana tropicalis Nieuwkoop and Faber (NF) stage 46 embryos. S. tropicalis were exposed to progesterone (P4) from NF 12 to NF 46. The mRNA levels are expressed relative to the solvent control group and are normalized to the mean expression of elongation factor 1 alpha (ef1α), ribosomal protein L8 (rpl8) and ornithine decarboxylase (odc). Bars represent the mean mRNA level + SEM. Data were analyzed using one-way ANOVA (n = 7–8 per treatment, p < 0.05). Asterisks (*) indicate significant differences from the solvent control group (0.05% EtOH). The scales of the y-axes vary between graphs. C: water control, SC: solvent control (0.05% EtOH), ipgr: intracellular progesterone receptor, mpgrβ: membrane progesterone receptor beta, pgrmc1: progesterone receptor membrane component 1, ar: androgen receptor, erα: estrogen receptor alpha, srd5α1: steroid 5 alpha reductase type 1, srd5α2: steroid 5 alpha reductase type 2, srd5α3: steroid 5 alpha reductase type 3.
	Fig. 4. Effects of melengestrol acetate (MGA), on srd5α3 expression in Silurana tropicalis embryos. The mRNA levels are expressed relative to the control groups and are normalized to the mean expression of elongation factor 1 alpha (ef1α), ribosomal protein L8 (rpl8) and ornithine decarboxylase (odc). Bars represent the mean mRNA level + SEM. Data were analyzed using one-way ANOVA (n = 5–7 per treatment, p < 0.05). Asterisks (*) indicate significant differences from the solvent control group (0.05% EtOH). C: water control, SC: solvent control (0.05% EtOH), srd5α3: steroid 5 alpha reductase type 3.