Search bioRxiv⌕ Search

bioRxiv · 10.1101/166702

Progesterone regulates hypothalamic-pituitary-thyroid axis

Abstract

Progesterone is a natural steroid hormone excreted by animals and humans, which has been frequently detected in the aquatic ecosystems. The effects of the residual progesterone on fish are unclear. In this study, we aimed to examine the effects of progesterone on the hypothalamic-pituitary-thyroid (HPT) axis by detecting the gene transcriptional expression levels. Zebrafish embryos were treated with different concentrations of progesterone from 12 hours post-fertilization (hpf) to 120 hpf. Total mRNA was extracted and the transcriptional profiles of genes involved in HPT axis were examined using qPCR. The genes related to thyroid hormone metabolism and thyroid hormone synthesis were up-regulated in zebrafish exposed to progesterone. These results indicated that progesterone affected the mRNA expression of genes involved in the HPT axis, which might interrupt the endocrine system in zebrafish. Our data also suggested that zebrafish is a useful tool for evaluating the effects of chemicals on the thyroid endocrine system.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Zhong, C., Xiong, K., Wang, X.. 2017-07-21. Progesterone regulates hypothalamic-pituitary-thyroid axis. https://doi.org/10.1101/166702

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Target Specific Conformational Flexibility and Electrostatic Complementarity Modulate LTNF10 Peptide Binding to Phospholipase A2 Variants from Snake Venoms

Phospholipase A2 is one of the primary cytotoxins present in snake venoms, causing tissue damage through the hydrolysis of phospholipids in the cellular membrane. We prioritised and investigated in detail the binding and conformational dynamics of a ten-residue short peptide (LTNF10) from Lethal Toxin Neutralizing Factor from Opossum against snake venom Phospholipase A2 (svPLA2) variants. LTNF10 was prioritised from the curated list of peptide inhibitors. A charge-modulating mutation from aspartic acid to lysine at the fifth position in LTNF10 was observed to enhance the binding affinity to svPLA2 variants from Elapids. The mutant LTNF10 shows selectively enhanced binding affinity toward Group I svPLA2 from Elapidae. Free energy landscapes of LTNF10 and mutant LTNF10, and binding pocket-volume analysis of svPLA2 revealed that Lys5 substitution increases conformational flexibility of mutant LTNF10, allowing it to form favourable binding conformations, while svPLA2 shows a reduction in pocket volume. Conversely, the mutant LTNF10 shows reduced binding affinity in Group II svPLA2 from Viperidae while demonstrating reduced flexibility and a less significant decrease in binding pocket volume in svPLA2. These findings demonstrate that active-site charge microenvironments, binding pocket and structural differences in catalytically relevant loop regions influence LTNF10 binding to svPLA2. The differential binding affinity was primarily driven by improved non-covalent interactions, specifically reduced electrostatic repulsions and enhanced electrostatic interactions in Group I svPLA2 from Elapids. This was influenced by the enhanced flexibility of mutant LTNF10, suggesting the role of a complex scenario of enthalpy-entropy compensation. The understanding of dynamic and structural mechanisms of LTNF10 and svPLA2 interactions and binding offers key insights for designing target-specific peptide therapeutics against diverse svPLA2 toxins.

pharmacology and toxicology↗

Plasma untargeted metabolomics reveals distinct metabolic disturbances between sexes following inhalation of ultrafine particles and exposure to aircraft noise in mice

Traffic noise and air pollution, particularly ultrafine particles (UFP), are significantly associated with health risks. However, the systemic metabolic consequences of the combined effects of UFP and aircraft noise (AN) exposure on health remain poorly understood. We aimed to investigate changes in plasma metabolites in healthy wildtype C57BL/6J mice following whole-body inhalation exposure to UFP (average diameter <40 nm), AN and their combination (UFP+AN). Liquid chromatography-mass spectrometry (LC-MS)-based untargeted plasma metabolomics analysis was undertaken for UFP, AN, and combined UFP+AN-exposed mice of both sexes. This study identified a total of 1146 plasma metabolites. Across exposure groups, AN induced the greatest plasma metabolomic changes in both sexes, while UFP significantly altered metabolites only in females, indicating a sex-specific response. The combined UFP+AN exposure produced a modestly enhanced effect in males compared with either single exposure but showed an attenuated effect in females. Pathway analyses revealed that lipid and amino acid metabolism were the most affected, followed by xenobiotics, and cofactors and vitamins, after exposure in both female and male mice. Additionally, in the clean air control group, we identified sex differences in 49 plasma metabolites, which mostly included lipids and amino acids. Following exposure, however, sex-dependent metabolic differences became more pronounced and exposure-specific, suggesting that UFP and AN have distinct effects on plasma metabolome of male and female mice that extend beyond baseline sexual dimorphism observed in unexposed animals. To our knowledge, this study is the first comprehensive characterization of systemic metabolic changes in mice after combination of UFP and AN exposure, providing new insight into the interplay between traffic noise and air pollution health risks.

pharmacology and toxicology↗

Homoharringtonine targets XPC to inhibit DNA damage repair and sensitize tumors to platinum-based chemotherapy

DNA damage repair (DDR) is essential for preserving genomic stability and also represents a key targetable axis in cancer drug development. Here, we identify and validate homoharringtonine (HHT), a clinically approved antileukemic drug, as a novel DDR inhibitor using a phenotype-driven, high-content screen based on 53BP1 Tudor-domain foci formation. Mechanistically, HHT directly binds XPC, a critical nucleotide excision repair (NER) factor, with high affinity (Kd = 158.4 nM) in a manner dependent on Thr795 of XPC. HHT disrupts XPC-damaged DNA binding, impairs NER, and reduces non-homologous end joining (NHEJ) efficiency. Consequently, HHT sensitizes tumor cells to platinum-based chemotherapy in vitro and in vivo. These findings establish a phenotype-based platform for DDR inhibitor discovery, identify HHT as a first-in-class XPC inhibitor and uncover a previously unrecognized mechanism of HHT that may be exploited to enhance platinum-based therapy in solid tumors.

pharmacology and toxicology↗