Biology subjects

Williams, S.

Publications and source records attributed to Williams, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Coral reef habitat complexity decreases and diversifies local availability of light

The spatial distribution of environmental conditions can determine where organisms can and cannot live. When the distribution of microhabitats within a landscape is mediated by the shape of its surface, structural complexity can indirectly affect environmental niche distributions. This study investigates how light availability patterns change along a gradient of landscape complexity measured as surface rugosity and height range in tropical shallow reefs. We used 260,000 high frequency and high spatial resolution light measurements across 903 locations to determine the proportion of light that is available at the reef surface. We find that light available on the reef surface is highly variable, with close locations within reef sites experiencing up to 25.7 mol/m2d of daily photon input difference. After accounting for light attenuation due depth, light availability decreases with increasing surface rugosity: a unit increase in local surface rugosity corresponds to an 11-29% decrease in light availability. Local surface complexity can affect the distributions of light availability at local scales, while broader extent site metrics do not capture this variability. Our results suggest that structural complexity enhances local environmental variability, and its indirect effects on other environmental variables and their interactions are essential for understanding ecosystem processes.

ecology↗

bioRxiv2024

Attentional failures after sleep deprivation represent moments of cerebrospinal fluid flow

Sleep deprivation rapidly disrupts cognitive function, and in the long term contributes to neurological disease. Why sleep deprivation has such profound effects on cognition is not well understood. Here, we use simultaneous fast fMRI-EEG to test how sleep deprivation modulates cognitive, neural, and fluid dynamics in the human brain. We demonstrate that after sleep deprivation, sleep-like pulsatile cerebrospinal fluid (CSF) flow events intrude into the awake state. CSF flow is coupled to attentional function, with high flow during attentional impairment. Furthermore, CSF flow is tightly orchestrated in a series of brain-body changes including broadband neuronal shifts, pupil constriction, and altered systemic physiology, pointing to a coupled system of fluid dynamics and neuromodulatory state. The timing of these dynamics is consistent with a vascular mechanism regulated by neuromodulatory state, in which CSF begins to flow outward when attention fails, and flow reverses when attention recovers. The attentional costs of sleep deprivation may thus reflect an irrepressible need for neuronal rest periods and widespread pulsatile fluid flow.

neuroscience↗

bioRxiv2024

Patterns of crossover distribution in Drosophila mauritiana necessitate a re-thinking of the centromere effect on crossing over

We present a SNP-based crossover map for Drosophila mauritiana. Using females derived by crossing two different strains of D. mauritiana, we analyzed crossing over on all five major chromosome arms. Analysis of 105 male progeny allowed us to identify 327 crossover chromatids bearing single, double, or triple crossover events, representing 398 separate crossover events. We mapped these crossover sites along these five chromosome arms using a genome sequence map that includes the euchromatin-heterochromatin boundary. Confirming previous studies, we show that the overall crossover frequency in D. mauritiana is higher than is seen in D. melanogaster. Much of the increase in exchange frequency in D. mauritiana is due to a greatly diminished centromere effect. Using larval neuroblast metaphases from D. mauritiana -D. melanogaster hybrids we show that the lengths of the pericentromeric heterochromatin do not differ substantially between the two species, and thus cannot explain the observed differences in crossover distribution. Using a new and robust maximum likelihood estimation tool for obtaining Weinstein tetrad distributions, we observed an increase in bivalents with two or more crossovers when compared to D. melanogaster. This increase in crossing over along the arms of D. mauritiana likely reflects an expansion of the crossover-available euchromatin caused by the reduction in the centromere effect. The pattern of crossing over in D. mauritiana conflicts with the commonly accepted view of centromeres as polar suppressors of exchange (whose intensity is buffered by sequence non-specific heterochromatin) and demonstrates the importance of expanding such studies into other species of Drosophila. Article SummaryIn meiosis, homolog segregation is usually ensured by crossovers. The number and distribution of crossovers is in part regulated by cis-acting factors such as the cis- acting centromere effect, a polar suppression of exchange emanating from the vicinity of the centromere. We use SNP-based crossover mapping to show that in Drosophila mauritiana, the centromere effect is greatly reduced on four of the five major chromosome arms. We conclude that the centromere effect differs between Drosophila mauritiana and Drosophila melanogaster and that the ability to attenuate the centromere effect is not a general property of heterochromatin.

genetics↗

bioRxiv2024

Effects of non-invasive brain stimulation on effective connectivity during working memory task in Neurofibromatosis Type 1 patients

This study examined the effects of anodal transcranial direct current stimulation (atDCS) on effective connectivity during a working memory task. Eighteen adolescents with Neurofibromatosis Type 1 (NF1) completed a single{square}blind sham{square}controlled cross{square}over randomised atDCS trial. Dynamic causal modelling was used to estimate the effective connectivity between regions that showed working memory effects from the fMRI. Group-level inferences for between sessions (pre- and post-stimulation) and stimulation type (atDCS and sham) effects were carried out using the parametric empirical Bayes approach. A correlation analysis was performed to relate the estimated effective connectivity parameters of left dlPFC pre-atDCS and post-atDCS to the concentration of gamma-aminobutyric acid (GABA) measured via magnetic resonance spectroscopy (MRS-GABA). Next, correlation analysis was repeated using all working memory performance and all pre-atDCS and post-atDCS connectivity parameters. It was found that atDCS decreased average excitatory connectivity from left dorsolateral prefrontal cortex (dlPFC) to left superior frontal gyrus and increased average excitatory connectivity to left globus pallidus. Further, reduced average intrinsic (inhibitory) connectivity of left dlPFC was associated with lower MRS-GABA. However, none of the connectivity parameters of dlPFC showed any association with performance on a working memory task. These findings suggest that atDCS reorganised connectivity from frontal to fronto-striatal connectivity. As atDCS-related changes were not specific to the effect of working memory, they may have impacted general cognitive control processes. In addition, by reducing MRS-GABA, atDCS might make dlPFC more sensitive and responsive to external stimulation, such as performance of cognitive tasks. Highlights- atDCS was applied to left dlPFC in NF1 patients during working memory - After atDCS, no effect on modulatory connectivity - Evidence for increased N-back average connectivity from dlPFC to globus pallidus - Less dlPFC MRS-GABA was associated with less dlPFC inhibition

neuroscience↗

bioRxiv2024

Diversity and characteristics of the oral microbiome influenced by race and ethnicity

Periodontitis disproportionately affects racial/ethnic populations. Besides social determinants contributing to disparities in periodontal health, variations of oral microbial communities may also be a key factor influencing oral immune responses. To characterize the oral microbiome from different racial/ethnic populations, we collected 161 dental plaque samples from African Americans (AAs), Caucasian Americans (CAs), and Hispanic Americans (HAs) with clinical gingival health or biofilm-induced gingivitis on an intact periodontium. Using metagenomic sequencing, we found significant difference in diversity and abundance of microbial taxa in the dental plaque samples from AA, CA, and HA groups and unique microbial species that can only be detected in a particular racial/ethnic group. Moreover, we revealed racial/ethnic associated variations in functional potential of the oral microbiome, showing that diversity and abundance of antibiotic resistant genes were greater in the oral microbiome of the AAs than those in CAs or HAs, and that the AAs exhibited higher levels of genes involving in modification of glycoconjugates, oligo- and polysaccharides. These findings indicate more complex and higher virulence potential oral microbiome in AA and HA populations, which likely contributes to higher prevalence of periodontitis in AAs and HAs. ImportanceRecognizing the variations in the oral microbiome among racial/ethnic populations offers insight into the microbial determinants contributing to oral health disparities. In the study presented here, we found a higher level of bleeding on probing (BOP), an indicator of tissue inflammatory response, in the AA group, which is correspondence with a more complex oral microbiome detected in this group. Our observations suggest that the variations of the oral microbiome associated with racial/ethnic backgrounds may directly relate to their virulence potential including their abilities to induce host immune responses and to resist antibiotic treatment. Therefore, these finding can be a stepping stone for developing precision medicine and personalized periodontal prevention/treatment and for reducing oral health disparities.

microbiology↗

bioRxiv2024

Nuclear Histone H3 Post-translational Modification Profiling in Whole Cells using Spectral Flow Cytometry

Histone modifications play essential roles in regulating chromatin accessibility and downstream transcription, serving as critical determinants of cell identity and function. However, the diversity of histone post-translational modifications (PTMs) and their tendency to be studied in isolation limits our understanding of their coordinated roles in shaping cellular states. Conventional flow cytometry methods for histone PTM assessment suffer from low multiplexing capacity and typically require nuclear isolation, resulting in significant sample loss and an incomplete picture of the overall cell state. Here, we present EpiFlow, a spectral flow cytometry protocol designed for multiparametric analysis of histone PTMs within whole cells. By utilizing a 96-well plate format and preserving the cell entirely, EpiFlow improves throughput and efficiency while retaining sample integrity. This method resolves subtle variations in histone PTMs within neural progenitor cells, capturing distinct chromatin states across the cell cycle and correlating them with several markers. Furthermore, we provide an open-access GitHub repository containing detailed protocols and analysis workflows, ensuring reproducibility and accessibility of this approach. EpiFlow offers a robust framework for exploring chromatin dynamics, with broad implications for advancing fundamental research and therapeutic research.

developmental biology↗

bioRxiv2024

Structured and unstructured reactivations during REM sleep are modulated by novel experiences

Mammalian sleep alternates between rapid eye movement (REM) and non-REM (NREM) phases, each with distinct patterns of neural activity. The replay of waking experience during NREM sleep is a well-established substrate for memory consolidation, but whether comparable reactivation occurs during REM sleep has remained unclear, owing to the sparse firing that characterizes this state and the lack of robust methods for detecting replay within it. Here we combined calcium imaging with electrophysiology to monitor large populations of hippocampal CA1 neurons in mice and applied complementary analytical approaches to test for neural reactivation during REM sleep. We found that structured waking activity is re-expressed during REM sleep across a range of temporal organizations, from the reactivation of co-active cell assemblies to temporally ordered sequential replay. This reactivation was selectively shaped by the behavioral context of prior experience. Novel experience enhanced sequential replay and refined assembly composition, selectively reducing the participation of weakly contributing neurons; anxiogenic experience, by contrast, increased the frequency of assembly reactivation and reinforced the recruitment of strongly contributing neurons. REM sleep thus emerges as an active stage of memory processing that reorganizes recent experience according to its behavioral significance, engaging distinct operations for novel and for emotionally salient events.

neuroscience↗

bioRxiv2024

Predictive Coding of Reward in the Hippocampus

A fundamental objective of the brain is to anticipate future outcomes1-7. This process requires learning the states of the world as well as the transitional relationships between those states. The hippocampal cognitive map is believed to be one such internal model8. However, evidence for predictive coding9-12 and reward sensitivity13-19 in the hippocampal neuronal representation suggests that its role extends beyond purely spatial representation. In fact, it raises the question of what kind of spatial representation is most useful for learning and maximizing future rewards? Here, we track the evolution of reward representation over weeks as mice learn to solve a cognitively demanding reward-based task. Our findings reveal a highly organized restructuring of hippocampal reward representations during the learning process. Specifically, we found multiple lines of evidence, both at the population and single-cell levels, that hippocampal representation becomes predictive of reward over weeks. Namely, both population-level information about reward and the percentage of reward-tuned neurons decrease over time. At the same time, the representation of the animals choice and reward approach period (the period between choice and reward) increased over time. By tracking individual reward cells across sessions, we found that neurons initially tuned for reward shifted their tuning towards choice and reward approach periods, indicating that reward cells backpropagate their tuning to anticipate reward with experience. These findings underscore the dynamic nature of hippocampal representations, highlighting their critical role in learning through the prediction of future outcomes.

neuroscience↗

bioRxiv2024

Loss of cell junctional components and matrix alterations drive cell desquamation and fibrotic changes in Idiopathic Pulmonary Fibrosis

The distal bronchioles in Idiopathic Pulmonary Fibrosis (IPF) exhibit histopathological abnormalities such as bronchiolization, peribronchiolar fibrosis and honeycomb cysts that contribute to the overall architectural remodeling of lung tissue seen in the disease. Here we describe an additional histopathologic finding of epithelial desquamation in patients with IPF, wherein epithelial cells detach from the basement membrane of the distal bronchioles. To understand the mechanism driving this pathology, we performed spatial transcriptomics of the epithelial cells and spatial proteomics of the basement membrane of the distal bronchioles from IPF patients and patients with no prior history of lung disease. Our findings reveal a downregulation of cell junctional components, upregulation of epithelial-mesenchymal transition signatures and dysregulated basement membrane matrix in IPF distal bronchioles, facilitating epithelial desquamation. Further, functional assays identified regulation between Collagen IV in the matrix, and the junctional genes JUP and PLEC, that is crucial for maintaining distal bronchiolar homeostasis. In IPF, this balanced regulation between matrix and cell-junctions is disrupted, leading to loss of epithelial adhesion, peribronchiolar fibrosis and epithelial desquamation. Overall, our study suggests that in IPF the interplay between the loss of cell junctions and a dysregulated matrix results in desquamation of distal bronchiolar epithelium and lung remodeling, exacerbating the disease. One Sentence SummaryTwo-way regulation of cell junctional proteins and matrix proteins drives cellular desquamation and fibrosis in the distal bronchioles of patients with Idiopathic Pulmonary Fibrosis.

pathology↗

bioRxiv2024

Missense Mutant Gain-of-Function Causes Inverted Formin 2 (INF2)-Related Focal Segmental Glomerulosclerosis (FSGS)

Inverted formin-2 (INF2) gene mutations are among the most common causes of genetic focal segmental glomerulosclerosis (FSGS) with or without Charcot-Marie-Tooth (CMT) disease. Recent studies suggest that INF2, through its effects on actin and microtubule arrangement, can regulate processes including vesicle trafficking, cell adhesion, mitochondrial calcium uptake, mitochondrial fission, and T-cell polarization. Despite roles for INF2 in multiple cellular processes, neither the human pathogenic R218Q INF2 point mutation nor the INF2 knock-out allele is sufficient to cause disease in mice. This discrepancy challenges our efforts to explain the disease mechanism, as the link between INF2-related processes, podocyte structure, disease inheritance pattern, and their clinical presentation remains enigmatic. Here, we compared the kidney responses to puromycin aminonucleoside (PAN) induced injury between R218Q INF2 point mutant knock-in and INF2 knock-out mouse models and show that R218Q INF2 mice are susceptible to developing proteinuria and FSGS. This contrasts with INF2 knock-out mice, which show only a minimal kidney phenotype. Co-localization and co-immunoprecipitation analysis of wild-type and mutant INF2 coupled with measurements of cellular actin content revealed that the R218Q INF2 point mutation confers a gain-of-function effect by altering the actin cytoskeleton, facilitated in part by alterations in INF2 localization. Differential analysis of RNA expression in PAN-stressed heterozygous R218Q INF2 point-mutant and heterozygous INF2 knock-out mouse glomeruli showed that the adhesion and mitochondria-related pathways were significantly enriched in the disease condition. Mouse podocytes with R218Q INF2, and an INF2-mutant human patients kidney organoid-derived podocytes with an S186P INF2 mutation, recapitulate the defective adhesion and mitochondria phenotypes. These results link INF2-regulated cellular processes to the onset and progression of glomerular disease. Thus, our data demonstrate that gain-of-function mechanisms drive INF2-related FSGS and explain the autosomal dominant inheritance pattern of this disease.

genetics↗

bioRxiv2024

Characterization of immune cell populations in the tumor microenvironment of colorectal cancer using high definition spatial profiling

Colorectal cancer (CRC) is the second-deadliest cancer in the world, yet a deeper understanding of spatial patterns of gene expression in the tumor microenvironment (TME) remains elusive. Here, we introduce the Visium HD platform (10x Genomics) and use it to investigate human CRC and normal adjacent mucosal tissues from formalin fixed paraffin embedded (FFPE) samples. The first assay available on Visium HD is a probe-based spatial transcriptomics workflow that was developed to enable whole transcriptome single cell scale analysis. We demonstrate highly refined unsupervised spatial clustering in Visium HD data that aligns with the hallmarks of colon tissue morphology and is notably improved over earlier Visium assays. Using serial sections from the same FFPE blocks we generate a single cell atlas of our samples, then we integrate the data to comprehensively characterize the immune cell types present in the TME, specifically at the tumor periphery. We observed enrichment of two pro-tumor macrophage subpopulations with differential gene expression profiles that were localized within distinct tumor regions. Further characterization of the T cells present in one of the samples revealed a clonal expansion that we were able to localize in the tissue using in situ gene expression analysis. In situ analysis also allowed us to perform in-depth characterization of the microenvironment of the clonally expanded T cell population and we identified a third macrophage subpopulation with gene expression profiles consistent with an anti-tumor response. Our study provides a comprehensive map of the cellular composition of the CRC TME and identifies phenotypically and spatially distinct immune cell populations within it. We show that the single cell-scale resolution afforded by Visium HD and the whole transcriptome nature of the assay allows investigations into cellular function and interaction at the tumor periphery in FFPE tissues, which has not been previously possible.

cancer biology↗

bioRxiv2024

AHR activation accelerates the resolution of TGF-β1 induced fibroblast activation and promotes alveolar type 1 cell regeneration in alveolar organoids

Regeneration of the alveolar epithelium is necessary to restore tissue architecture and gas exchange capabilities in chronic pulmonary diseases such as fibrosing interstitial lung disease. While it is known alveolar type 2 (AT2) cells give rise to alveolar type 1 (AT1) cells to repair the alveolar epithelium after injury, methods to promote this process under pathological settings are poorly understood. Here, using a complex 3D organoid culture with TGF-{beta}1 dependent impaired AT1 spheroid formation, we performed a high-throughput screen (HTS) with [~]16,800 compounds to identify small molecules that increase number of AT1 spheroids. Longitudinal single cell RNA sequencing (scRNA-seq) revealed that DB-11-BE87 increased AT1 regeneration by reducing TGF-{beta}1 induced fibroblast activation, concurrently with AHR activation in those cells. These studies highlight a novel HTS system to identify factors that can promote AT1 differentiation and suggest AHR activation as a method to counteract pathological TGF-{beta}1 signaling in pulmonary disease.

cell biology↗

bioRxiv2024

Evaluating a Novel High-Density EEG Sensor Net Structure for Improving Inclusivity in Infants with Curly or Tightly Coiled Hair

Electroencephalography (EEG) is an important tool in the field of developmental cognitive neuroscience for indexing neural activity. However, racial biases persist in EEG research that limit the utility of this tool. One bias comes from the structure of EEG nets/caps that do not facilitate equitable data collection across hair textures and types. Recent efforts have improved EEG net/cap design, but these solutions can be time-intensive, reduce sensor density, and are more difficult to implement in younger populations. The present study focused on testing EEG sensor net designs over infancy. Specifically, we compared EEG data quality and retention between two high-density saline-based EEG sensor net designs from the same company (Magstim EGI, Whitland, UK) within the same infants during a baseline EEG paradigm. We found that within infants, the tall sensor nets resulted in lower impedances during collection, including lower impedances in the key online reference electrode for those with greater hair heights and resulted in a greater number of usable EEG channels and data segments retained during pre-processing. These results suggest that along with other best practices, the modified tall sensor net design is useful for improving data quality and retention in infant participants with curly or tightly-coiled hair.

neuroscience↗

bioRxiv2024

DNA methylation machinery is involved in development and reproduction in the viviparous pea aphid (Acyrthosiphon pisum).

The pea aphid (Acyrthosiphon pisum) like the majority of extant aphids displays cyclical parthenogenesis - the ability of mothers to switch the reproductive mode of their offspring from reproducing parthenogenetically to sexually in response to environmental cues. The pea aphid genome encodes two paralogs of the de novo DNA methyltransferase gene, dnmt3a and dnmt3x. Here we show, using phylogenetic analysis, that this gene duplication event occurred at least 106 million years ago, likely after the divergence of the lineage leading to the Aphidomorpha (aphids, phylloxera and adelgids) from that leading to the scale insects (Coccoidea) and that the two paralogs are maintained in the genomes of all aphids examined. We also show that the mRNA of both dnmt3 paralogs are maternally expressed in the viviparous aphid ovary. During development both paralogs are expressed in the germ cells of embryos beginning at stage 5 and persisting throughout development. Chemical inhibition of the DNA methylation machinery leads to defects of oocytes and early stage embryos, and causes a proportion of later stage embryos to be born dead or die soon after birth. These phenotypes suggest a role for DNA methyltransferases in reproduction, consistent with that seen in other insects. Taking the vast evolutionary history of the dnmt3 paralogs, and the localization of their mRNAs in the ovary, we suggest there is a role for dnmt3a and/or dnmt3x in early development, and a role for DNA methylation machinery in reproduction and development of the viviparous pea aphid.

developmental biology↗

bioRxiv2024

The human complement factor B-C3b complex: Investigation of the interaction using C3b bound to thiol-Sepharose

Factor B, a serine protease proenzyme and part of the complement system, binds to other complement proteins such as C3b and properdin. While it is known to be activated by factor D, other interactions that interfere with the binding between Factor B and C3b are less well-understood. We attached C3b to a thiol Sepharose via its free SH group and conducted a competition assay employing 125I-labelled factor B to study competitive binding. Two anti-C3d monoclonal antibodies (F49b and 4C2) were found to partially inhibit the binding of Factor B to C3b. The inhibitory effects of these monoclonal antibodies were found to be dose-dependent. 4C2 was found to have a maximum inhibition of 50%, while the maximum inhibition by F49b was [~]40%. In contrast, two anti-C3c monoclonal antibodies (F39b and F20b) were able to enhance the formation of the factor B-C3b complex in a dose-dependent manner. Competition binding studies with isolated C3 fragments further supported the involvement of the C3d region in factor B binding, as C3d inhibited the binding of factor B to C3b completely. Furthermore, additional competition binding studies conducted with each of the three domains of factor B (Ba, vWF and SP) demonstrated that each domain independently inhibited the binding of intact factor B to C3b by [~]50%.

immunology↗

bioRxiv2023

Anhedonia severity mediates the relationship between attentional networks recruitment and emotional blunting during music listening

Recent studies have reported atypical emotional processing in individuals with greater levels of anhedonic depressive symptoms. However, the relationship between brain networks dynamics and moment-to-moment affective responses to naturalistic paradigms, as emotions are unfolding, remains unclear. In this study, we used the unique temporal characteristics of music to investigate behavioural and brain network dynamics as a function of anhedonic depressive symptoms severity in healthy adults during an emotionally provocative music listening task. Thirty-one neurotypical participants aged 18-30 years were required to continuously rate happy, neutral and sad pieces of music whilst undergoing MRI scanning. They were also asked to fill in questionnaires assessing their levels of anhedonic depressive symptoms. Using a novel fMRI analysis method called Leading Eigenvector Dynamics Analysis (LEiDA), we found an increased probability of occurrence of attentional networks and a blunted emotional response to both happy and sad pieces of music in participants with greater levels of anhedonic depressive symptoms. More specifically, anhedonic depressive symptoms mediated the relationship between attentional networks recruitment and emotional blunting. Furthermore, the elevated recruitment of attentional networks during emotional pieces of music carried over into subsequent neutral music. Future studies are needed to investigate whether these findings could be generalised to a clinical population (i.e., Major Depressive Disorder).

neuroscience↗

bioRxiv2023

Predicting Anorexia Nervosa and Autistic Characteristics in Individuals with Anorexia Nervosa from Resting State Cyclic Connectivity.

BackgroundResting state functional Magnetic Resonance Imaging (rsfMRI) differences have been reported in individuals with anorexia nervosa (AN). However, methodological issues limit inferences, the dynamic cyclic nature of the resting state signal has not been explored, neither has the association with known elevated autistic characteristics. Methods92 participants, 65 Individuals with AN and 27 controls underwent rsfMRI. Cyclic analysis was conducted to obtain pairwise relationships between regions. Classification of group and regression to predict autistic characteristics within the AN group was conducted, with model weights being explored to ascertain the most predictive pairwise relationships. ResultsPairwise relationships in the temporal, dorsal and ventral attention networks were most predictive of group. The anterior intraparietal sulcus, salience, dorsal attention, auditory dorsal posterior cingulate cortex, and ventral attention networks were most predictive of autistic characteristics. DiscussionSeveral distinct pairwise relationships predicting group and autistic characteristics were found, however, the global disruption of the temporal ordering of the cyclic wave, and variation in temporal ordering across resting state scan are also a neurophenotype in individuals with AN and the relationship to autistic characteristics. Characteristics associated with AN and autism are also predicted by distinct neural regions.

neuroscience↗

bioRxiv2023

Metformin and guanylurea reduce survival, but have limited sublethal effects in larval zebrafish (Danio rerio)

Metformin is the most common first-line oral therapeutic agent used in the treatment of type-2 diabetes, one of the most prevalent chronic diseases in North America. Post excretion, the compound enters wastewater treatment plants where it is partially bio-transformed by bacteria into guanylurea. Both metformin and guanylurea enter freshwater environments in wastewater effluent where they are available for uptake by aquatic biota. However, our understanding of the effects of metformin and guanylurea on aquatic life is limited. We tested the hypothesis that metformin and guanylurea can influence the development of zebrafish (Danio rerio), by assessing morphometrics, cardiac development, energetic state, and behaviour of early larvae. Embryos were exposed to environmentally relevant (0.4, 4, 40 g{middle dot}L-1) and supra-environmental (400 and 4000 g{middle dot}L-1) concentrations of metformin and guanylurea from the 4-cell stage (3 hours post fertilization; hpf), until first feed (120 hpf). Exposures to 40 g{middle dot}L-1and higher of both metformin and guanylurea increased mortality. Metformin delayed hatching at the highest concentration tested (4000 g{middle dot}L-1). The incidence of spinal curvature increased with exposure to both chemicals at supra-environmental levels (400 and 4000 g{middle dot}L-1 for metformin; 400 g{middle dot}L-1 for guanylurea). Metformin and guanylurea exposure imposed slight bradycardia in early development, but did not alter oxygen consumption, ATP levels, carbohydrate levels, general swimming, light-dark movement, startle response, or thigmotaxis, irrespective of exposure concentration. The results suggest similar and low sensitivities of larval fish to both metformin and guanylurea. Apart from a small increase in mortality, these compounds impart a modest impact to the early-life stages of zebrafish that are largely limited to supra-environmental concentrations.

pharmacology and toxicology↗