Biology subjects

Hogstrand, C.

Publications and source records attributed to Hogstrand, C..

4 recordsLinked to original sources

bioRxiv2026

Deficiency of the membrane androgen receptor ZIP9 alters brain zinc distribution, reproductive endocrinology, and female fertility

Zinc is an essential trace element involved in numerous biological processes, including cellular signalling, development, and reproduction. Zinc homeostasis is regulated by zinc transporters, yet the physiological roles of many transporters remain poorly understood in vivo. Here, we investigated the function of the zinc transporter ZIP9 (SLC39A9) using a zebrafish (Danio rerio) knockout model. Elemental imaging using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) revealed altered zinc distribution in zip9-deficient larvae. Synchrotron-based X-ray fluorescence (XRF) imaging further showed reduced zinc levels in the brain region of mutant zebrafish. Consistent with these observations, loss of zip9 was associated with altered expression of key neuroendocrine genes within the hypothalamic-pituitary-gonadal (HPG) axis. Zip9 mutant females exhibited disrupted ovarian follicle development, reduced spawning rates, and decreased egg production. In addition, embryos derived from zip9 mutant parents displayed reduced size, impaired early development, and decreased survival. Together, these findings identify ZIP9 as a regulator of zinc distribution in vivo and suggest that ZIP9-mediated zinc signalling contributes to reproductive regulation in zebrafish.

physiology↗

bioRxiv2025

Predicting Organ-Specific Toxicity of Selective Androgen Receptor Modulators, using Transfer Learning on Graph Convolutional Networks

Novel Quantitative Structure-Activity Relationship (QSAR) models were constructed using Graph Convolutional Networks (GCNs), to predict Drug-Induced Liver Injury (DILI), Drug-Induced Renal Injury (DIRI) and Drug-Induced Cardiotoxicity (DICT) of Selective Androgen Receptor Modulators (SARMs) - an emerging class of performance-enhancing drugs. Prior to training on DILI, DIRI and DICT datasets, the GCN QSAR models were first pre-trained on a variety of unrelated biomedical assay datasets, as an attempt to improve model performance via transfer learning. The success of the transfer learning was mixed; model performances were measurably improved via pre-training on certain datasets, by statistically weak increases. The optimal final QSAR models achieved overall accuracy scores of 68% for DILI (no significant improvement via ensemble modelling), 76% for DIRI (improved to 77% via ensemble modelling) and 65% for DICT (improved to 67% via ensemble modelling). Application of the most optimal singular models to a dataset of 25 SARMs predicted that 21 of the 25 SARMs are either DILI-positive, DIRI-positive, or both - which raises concern, given the rising use of SARMs. All SARMs except for one were predicted as DICT-negative. A novel definition of the Applicability Domain (AD) was used, intended for close relevance to the models, via generating three-dimensional graph embeddings, for each model. Convex hulls were fitted around training data embeddings, with a {+/-}10% buffer, defining the AD as the region of embedded chemical space covered by the convex hull, for a given model. Subsequent analysis found that a majority of DILI, DIRI and DICT testing data lay within the AD, alongside a majority of the SARMs - adding consensus to the reliability of the predictions.

pharmacology and toxicology↗

bioRxiv2025

Structures and zinc ion transport pathways of the human SLC39A family of metal transporters

The SLC39A (ZIP) family of zinc ion transporters play a pivotal role in maintaining zinc homeostasis, which is essential for numerous physiological processes involving enzyme catalysis, protein structure and regulation in signal transduction. This investigation employed AlphaFold3 to predict and analyze the 3D structures of all 14 human ZIP family members and revealed key structural and functional features, including transmembrane domains with eight alpha-helices, extracellular and cytoplasmic domains, dimerization, and zinc ion transport pathways. Unique zinc-binding motifs--composed of histidine, aspartic acid, and glutamic acid--were identified. They facilitate zinc ion attraction, selection, and transport. The findings highlight significant structural diversity in these proteins, with additional alpha-helices, disulfide bonds, and other conserved motifs that together contribute to functional specialization across the ZIP family members. Compared to predictions, which exist only for ZIP4, the models incorporate dimeric structures, rationalize loop conformations, and achieve a higher resolution. The predicted 3D structures offer enhanced insights into zinc ion transport mechanisms and provide a foundation for future research into the structural biology of these proteins and their interacting partners in physiology and pathology.

biochemistry↗

bioRxiv2022

Aryl hydrocarbon receptor utilises cellular zinc signals to maintain the gut epithelial barrier

Both zinc and plant-derived ligands of the aryl hydrocarbon receptor (AHR) are dietary components which regulate intestinal epithelial barrier function and protect against Inflammatory Bowel Disease (IBD)1,2. Here, we explore whether zinc and AHR pathway are linked using a mouse IBD model with follow-on studies on human and mouse ileum organoids. Our data demonstrate that AHR regulates cellular zinc uptake, and that zinc is an integral part of AHR signalling processes. We show that dietary supplementation in mice with the plant-derived AHR ligand precursor, indole-3-carbinol (I3C), offers a high level of protection against dextran sulfate sodium induced IBD while protection fails in mice with AHR deleted in the intestinal epithelium. AHR agonist treatment is also ineffective in mice with a nutritional zinc deficiency. Experiments in the human Caco-2 cell line and ileum organoids showed that AHR activation increases total cellular zinc and cytosolic free Zn2+ concentrations through transcriptional upregulation of several SLC39 zinc importers. As a consequence, genes for tight junction (TJ) proteins were upregulated in a zinc-dependent manner involving zinc inhibition of signalling to NF-{kappa}B and attenuated degradation of TJ proteins through zinc inhibition of calpain activity. Thus, our data indicate that AHR activation by plant-derived dietary ligands improves gut barrier function via zinc-dependent cellular pathways, suggesting that combined dietary supplementation with AHR ligands and zinc might be effective in preventing and treating inflammatory gut disorders.

cell biology↗