Biology subjects

Huayta, J.

Publications and source records attributed to Huayta, J..

7 recordsLinked to original sources

bioRxiv2026

Sodium arsenite requires redox sensitization to cause developmental dopaminergic neurotoxicity in Caenorhabditis elegans

Environmental pollutants can disrupt mitochondrial function through many pathways and mitochondrial dysfunction is often linked to neurotoxicity, particularly of dopaminergic neurons. However, there are many mechanisms of mitochondrial toxicity. Remarkably, despite the centrality of the Krebs cycle to mitochondrial bioenergetics, there is very limited evidence regarding whether pollutants that inhibit the Krebs cycle can cause neurotoxicity. We exposed Caenorhabditis elegans through its whole development to Krebs cycle inhibitors sodium arsenite and fluoroacetic acid, and evaluated neuronal morphology and function as well as dopaminergic ATP levels and redox state. Both chemicals impaired growth and reproduction, but neither caused morphological damage nor functional deficits in dopaminergic, glutamatergic, or cholinergic neurons at concentrations causing mild organismal toxicity. Sodium arsenite, but not fluoroacetic acid, decreased dopaminergic ATP levels; neither caused significant changes in mitochondrial redox state. However, developmental exposure to sodium arsenite caused dopaminergic neurotoxicity when mitochondrial quality control or redox stress response was compromised by loss of pink-1/PINK1 or sod-2/SOD2, by co-exposure to rotenone, antimycin A, or buthionine sulfoximine, or secondary challenge to 6-hydroxydopamine. These conditions also led to dopamine-associated behavioral deficits. Thus, developmental exposure to sodium arsenite required an additional mitochondrial or redox stress challenge to cause dopaminergic neurotoxicity, and we did not find evidence that inhibition of the Krebs cycle broadly defined causes developmental neurotoxicity.

pharmacology and toxicology↗

bioRxiv2026

Evidence from three taxonomically distinct species for a non-AhR mechanism of developmental neurotoxicity of an environmentally derived mixture of polycyclic aromatic hydrocarbons

Typical environmental exposures to the toxic class of chemicals known as polycyclic aromatic hydrocarbons (PAHs) involve complex mixtures; however, relatively few mechanistic toxicity studies have evaluated them as environmental mixtures, instead focusing on individual compounds or simple mixtures. In this study, we first derived Republic Sediment Extract (REPSE), a complex PAH mixture extracted from sediment at the Republic Creosoting site of the Elizabeth River in Norfolk, Virginia. After characterizing the PAH contents of REPSE, we evaluated its mechanisms of developmental neurotoxicity in three evolutionarily distinct taxa, leveraging the unique strengths of Atlantic killifish, zebrafish, and Caenorhabditis elegans as model species, with a focus on the Aryl hydrocarbon Receptor (AhR) pathway. Embryonic REPSE exposure caused induction of CYP1A in both fish species at sub-teratogenic concentrations, consistent with activation of the canonical AhR pathway. These sub-teratogenic exposures nevertheless induced neurotoxicity across both fish species, altering neurobehavioral phenotypes in fish, and induced dopaminergic neuronal damage in worms, again at non-teratogenic concentrations. To determine whether these effects were linked to canonical AhR response pathways, we examined killifish offspring from the pollution-adapted Republic Creosoting population, which exhibited characteristic recalcitrance to CYP1A induction, but remained susceptible to the neurobehavioral effects of REPSE. The induction of neuronal damage in worms provides orthogonal evidence for a non-AhR mechanism, because C. elegans AhR is not transcriptionally activated by PAHs as in vertebrates. Further probing of potential mechanisms underlying REPSE-induced neurotoxicity in worms revealed altered neuronal redox status (roGFP) and energy availability (ATP:ADP ratio). Collectively, our multispecies approach reveals conserved mechanisms of PAH mixture neurotoxicity, including effects that extend beyond canonical AhR signaling.

pharmacology and toxicology↗

bioRxiv2025

Inhibition of Mitochondrial Complex III Causes Dopaminergic Neurodegeneration by Redox Stress in Caenorhabditis elegans

Environmental factors including chemical exposures are important contributors to Parkinsons disease (PD). Nearly all well-validated chemicals involved in PD affect mitochondria, and the great majority of those identified inhibit mitochondrial complex I, causing ATP depletion and oxidative stress. We hypothesized that inhibition of mitochondrial complex III would also cause dopaminergic neurotoxicity. Using Caenorhabditis elegans to evaluate the in vivo effects of complex III-inhibiting pesticides antimycin A and pyraclostrobin, we found that both caused selective dopaminergic neurotoxicity. We evaluated exacerbation of dopaminergic neurotoxicity by the presence of -synuclein, and pdr-1/PRKN and pink-1/PINK1 mutant backgrounds and found increased neurotoxicity for pdr-1. Complex III inhibition caused a more-oxidized cellular environment in those neurons and pharmacological and genetic antioxidant interventions rescued neurotoxicity, but energetic rescue attempts did not. Finally, optogenetic production of superoxide anion specifically at complex III caused dopaminergic neuronal damage. Thus, redox stress at complex III following chemical exposure causes dopaminergic neurotoxicity in vivo in C. elegans.

pharmacology and toxicology↗

bioRxiv2025

Assessment of developmental neurotoxicology-associated alterations in neuronal architecture and function using Caenorhabditis elegans

Few of the many chemicals that regulatory agencies are charged with assessing for risk have been carefully tested for developmental neurotoxicity (DNT). To speed up testing efforts, as well as to reduce the use of vertebrate animals, great effort is being devoted to alternate laboratory models for testing DNT. A major mechanism of DNT is altered neuronal architecture resulting from chemical exposure during neurodevelopment. Caenorhabditis elegans is a nematode that has been extensively studied by neurobiologists and developmental biologists, and to a lesser extent by neurotoxicologists. The developmental trajectory of the nervous system in C. elegans is easily visualized, normally entirely invariant, and fully mapped. Therefore, we hypothesized that C. elegans could be a powerful in vivo model to test chemicals for the potential to alter developmental patterning of neuronal architecture. To test whether this might be true, we developed a novel C. elegans DNT testing paradigm that includes exposure throughout development, examines all major neurotransmitter neuronal types for architectural alterations, and tests behaviors specific to dopaminergic, cholinergic, and glutamatergic functions. We used this paradigm to characterize the effects of early-life exposures to the developmental neurotoxicants lead, cadmium, and benzo(a)pyrene (BaP) on dopaminergic, cholinergic, and glutamatergic architecture. We also assessed whether exposures would alter neuronal specification as assessed by expression of reporter genes diagnostic of specific neurotransmitters. We identified no cases in which the apparent neurotransmitter type of the neurons we examined changed, but many in which neuronal morphology was altered. We also found that neuron-specific behaviors were altered during C. elegans mid-adulthood for populations with measured morphological neurodegeneration in earlier stages. The functional changes were consistent with the morphological changes we observed in terms of type of neuron affected. We identified changes consistent with those reported in the mammalian DNT literature, strengthening the case for C. elegans as a DNT model, and made novel observations that should be followed up in future studies.

pharmacology and toxicology↗

bioRxiv2023

Morphological hallmarks of dopaminergic neurodegeneration are associated with altered neuron function in Caenorhabditis elegans

Caenorhabditis elegans (C. elegans) is an excellent model system to study neurodegenerative diseases, such as Parkinsons disease, as it enables analysis of both neuron morphology and function in live animals. Multiple structural changes in neurons, such as cephalic dendrite morphological abnormalities, have been considered hallmarks of neurodegeneration in this model, but their relevance to changes in neuron function are not entirely clear. We sought to test whether hallmark morphological changes associated with chemically induced dopaminergic neuron degeneration, such as dendrite blebbing, breakage, and loss, are indicative of neuronal malfunction and result in changes in behavior. We adapted an established dopaminergic neuronal function assay by measuring paralysis in the presence of exogenous dopamine, which revealed clear differences between cat-2 dopamine deficient mutants, wildtype worms, and dat-1 dopamine abundant mutants. Next, we integrated an automated image processing algorithm and a microfluidic device to segregate worm populations by their cephalic dendrite morphologies. We show that nematodes with dopaminergic dendrite degeneration markers, such as blebbing or breakage, paralyze at higher rates in a dopamine solution, providing evidence that dopaminergic neurodegeneration morphologies are correlated with functional neuronal outputs.

neuroscience↗

bioRxiv2021

Endogenous DAF-16 Spatiotemporal Activity Quantitatively Predicts Lifespan Extension Induced by Dietary Restriction

In many organisms, dietary restriction (DR) leads to lifespan extension through the activation of cell protection and pro-longevity gene expression programs. In the nematode C. elegans, the DAF-16 transcription factor is a key aging regulator that governs the Insulin/IGF-1 signaling pathway and undergoes translocation from the cytoplasm to the nucleus of cells when animals are exposed to food limitation. In this work, we assess the endogenous activity of DAF-16 under various DR regimes by coupling CRISPR/Cas9-enabled fluorescent tagging of DAF-16 with quantitative image analysis and machine learning. Our results indicate that lifelong DAF-16 endogenous activity is a robust predictor of mean lifespan in C. elegans, and it accounts for 78% of the lifespan variability induced by DR. We found that this lifespan-extending mechanism occurs mainly in the intestine and neurons, and that DR drives DAF-16 activity in unexpected locations such as the germline and intestinal nucleoli.

systems biology↗

bioRxiv2021

Antagonistic effects of chemical mixtures on the oxidative stress response are silenced by heat stress and reversed under dietary restriction

Chemical agents released into the environment can induce oxidative stress in organisms, which is detrimental for health. Although environmental exposures typically incorporate multiple chemicals, organismal studies on oxidative stress derived from chemical agents commonly study exposures to individual compounds. In this work, we explore how chemical mixtures drive the oxidative stress response under various conditions in the nematode C. elegans, by quantitatively assessing levels of gst-4 expression. Our results indicate that naphthoquinone mixtures drive responses differently than individual components, and that altering environmental conditions, such as increased heat and reduced food availability, result in dramatically different oxidative stress responses mounted by C. elegans. When exposed to heat, the oxidative stress response is diminished. Notably, when exposed to limited food, the oxidative stress response specific to juglone is significantly heightened, while identified antagonistic interactions between some naphthoquinone components in mixtures are abolished. This implies that organismal responses to xenobiotics is confounded by environment and stressor interactions. Given the high number of variables under study, and their potential combinations, a simplex centroid design was used to capture such non-trivial response over the design space. This makes the case for the adoption of Design of Experiments approaches as they can greatly expand the experimental space probed in noisy biological readouts, and in combinatorial experiments. Our results also reveal gaps in our current knowledge of the organismal oxidative stress response, which can be addressed by employing sophisticated design of experiments approaches to identify significant interactions.

physiology↗