Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/146092

TDCPP exposure affects the concentrations of thyroid hormones in zebrafish

Song, J.
View original source ↗Export metadata ↓

Abstract

Previous studies show that TDCPP may interrupt the thyroid endocrine system, however, the potential mechanisms involved in these processes were largely unknown. In this study, zebrafish embryos/larvae were exposed to TDCPP until 120 hpf, by which time most of the organs of the larvae have completed development. In this study, the effects of TDCPP on HPT axis were examined and the thyroid hormone levels were measured after TDCPP treatment. Zebrafish (Danio rerio) embryos were treated with a series concentration of TDCPP (10, 20, 40, 80, 160 and 320 g/L) from 1 day post-fertilization (dpf) to 5 dpf. Exposure concentrations of TDCPP were determined based on the survival rates in each group. Total mRNA were isolated, first-strand cDNA were synthesis and qPCR were performed to detect the mRNA expression levels in hypothalamic-pituitary-thyroid (HPT) axis. The mRNA expression levels of genes involved in thyroid hormone homeostasis were increased in the TDCPP-treated larvae. The mRNA levels of genes involved in thyroid hormone synthesis were also increased in the embryos treated with TDCPP. Furthermore, exposure to TDCPP led to a dose-dependent effect on zebrafish development, including diminished hatching and survival rates, increased malformation. TDCPP treatment significantly reduced the T4 concentration in the 5 dpf zebrafish larvae, but increased the concentration of T3, suggesting the function of thyroid endocrine were interrupted in the TDCPP-exposed zebrafish. Taken together, these data indicated that TDCPP affected the thyroid hormone levels in the zebrafish larvae and could increased the mRNA expression levels of genes related to HPT axis, which further impaired the endocrine homeostasis and thyroid system.

Explore related subjects

pharmacology and toxicologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Song, J.. 2017-07-18. TDCPP exposure affects the concentrations of thyroid hormones in zebrafish. https://doi.org/10.1101/146092

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

KEEP EXPLORING

Related preprints

bioRxiv2026

The collective effect of non-nicotine constituents on the reinforcing and neuropharmacological effects of comprehensive cigarette smoke and electronic nicotine delivery system (ENDS) aerosol extracts in rats.

Tobacco product extracts containing nicotine and non-nicotine constituents are useful for understanding the collective role of these constituents in tobacco use disorder (TUD). However, few studies have used extracts with both water-soluble and non-water-soluble constituents with accompanying chemical analysis, or compared behavioral and neuropharmacological effects across product types. To address these limitations, we compared the relative abuse liability of cigarette smoke (CS) and electronic nicotine delivery system (ENDS) aerosol (EA) extracts to nicotine alone using intravenous self-administration in rats, and examined effects on nucleus accumbens (NAc) dopamine (DA) release and binding/function at nicotinic acetylcholine receptors (nAChRs) and other addiction-related receptors in vitro. CS extract contained higher levels of several behaviorally active non-nicotine constituents than EA extract. Both extracts produced a downward/leftward shift in the descending limb of the unit dose-response curve relative to nicotine alone, while only CS extract produced greater compensatory increases in responding compared to nicotine alone. Demand intensity (Q0) was lower for CS but not EA extract, relative to nicotine alone, whereas demand elasticity for both extracts was similar to nicotine alone. Stress-induced reinstatement was comparable between CS extract and nicotine alone but attenuated for EA extract. CS extract, but not EA extract, showed greater potency for 4{beta}2 nAChR activation and substantial binding across numerous non-nAChRs (DA, serotonergic, opioid) relative to nicotine alone at a high screening concentration. CS extract, but not nicotine alone, also inhibited cyclooxygenase (COX)-1 and -2 at smoking-relevant concentrations. There was no difference in NAc DA release between formulations. These findings indicate non-nicotine constituents contribute to certain reinforcing and neuropharmacological effects of CS, and to a lesser extent EA. Our finding of COX inhibition by CS extract warrants further investigation as a potential mechanism contributing to the effects of CS and TUD.

pharmacology and toxicology↗
bioRxiv2026

Fragment Covalent Bond Formation at SOS1 Tyr-884 Inhibits KRAS Nucleotide Exchange

The activation of the KRAS oncogene from its inactive GDP-bound state to its active GTP-bound state is mediated by Son of Sevenless (SOS) exchange factors. Small-molecule inhibition of SOS1 has been achieved, with three compounds currently in clinical trials. These compounds bind to SOS1 and disrupt a crucial interaction between SOS1 Tyr-884 and KRAS Arg-73. Here, we screen libraries of aryl sulfonyl fluorides to explore covalent bond formation at Tyr-884 as a strategy for covalent inhibition of SOS1-KRAS binding. Initially, ten fragments were tested and several inhibited KRAS nucleotide exchange by SOS1. X-ray crystal structures revealed that one reaction site for the fragments was Tyr-884, but mass spectrometry and nucleotide exchange assays with wild-type and mutant SOS1 indicated additional reaction sites. To identify candidates specific to Tyr-884, we conducted a larger screen and identified fragment 11 (SOF-599). The fragment formed an adduct predominantly at Tyr-884 and inhibited KRAS nucleotide exchange by SOS1 in a time- and concentration-dependent manner. Fragment 11 (SOF-599) exhibited a half-maximal inactivation concentration (KI) of 12 micromolar and a reaction half-life of 6 h. These findings establish 11 (SOF-599) as a promising starting point for the development of covalent SOS1 inhibitors as an alternative strategy to existing non-covalent antagonists.

pharmacology and toxicology↗
bioRxiv2026

Vorinostat Can Reduce an Ongoing Fibrosis and Preserve Key Liver Metabolic Functions by Selectively Altering Mesenchymal Cell Differentiation

Liver fibrosis is a major global cause of mortality that is driven by the activation of hepatic stellate cells (HSCs) into extracellular matrix (ECM)-producing myofibroblasts (MyoFs). The lack of predictive human in vitro models has severely hampered the discovery of targeted anti-fibrotic therapies. Here, we describe a human iPSC-derived hepatic micro-organoid (microHO) model, which labels collagen producing cells, to study liver fibrosis pathophysiology and screen drug candidates. We discovered that while multiple drugs prevented fibrosis when co-administered prophylactically with TGF{beta}1, only the FDA-approved pan-HDAC inhibitor Vorinostat (SAHA) successfully reduced an established, ongoing fibrosis and preserved life-sustaining liver metabolic functions in a fibrotic microenvironment, including ammonia detoxification and CYP3A4-mediated drug metabolism. To uncover its mechanism of action, we utilized single-cell RNA sequencing and CRISPR-Cas12a lineage tracing. We found that Vorinostat actively redirects HSC differentiation away from pro-fibrotic MyoFs and toward a distinct, fibrosis-suppressing mesenchymal inhibitory (MesInh) cell. By reversing TGF{beta}1-induced epigenetic silencing, Vorinostat opens condensed chromatin to rescue metabolic gene expression and generates anti-fibrotic effectors that neutralize ongoing TGF{beta}1 signaling. Given its distinct capacity to remodel mesenchymal cell fate and reverse epigenetic repression of metabolic genes at clinically achievable concentrations, Vorinostat represents a highly promising drug for repurposing as a therapeutic for advanced human liver fibrosis.

pharmacology and toxicology↗