Tavernier N et al. (2015) Exp Cell Res "Cell cycle timing regulation during asynchronous divisions of the early C. elegans embryo."

Tavernier N, Labbe JC, Pintard L

[Exp Cell Res, 2015]

A fundamental question in developmental biology is how different cell lineages acquire different cell cycle durations. With its highly stereotypical asymmetric and asynchronous cell divisions, the early Caenorhabditis elegans embryo provides an ideal system to study lineage-specific cell cycle timing regulation during development, with high spatio-temporal resolution. The first embryonic division is asymmetric and generates two blastomeres of different sizes (AB>P1) and developmental potentials that divide asynchronously, with the anterior somatic blastomere AB dividing reproducibly two minutes before the posterior germline blastomere P1. The evolutionarily conserved PAR proteins (abnormal embryonic PARtitioning of cytoplasm) regulate all of the asymmetries in the early embryo including cell cycle asynchrony between AB and P1 blastomeres. Here we discuss our current understanding and open questions on the mechanism by which the PAR proteins regulate asynchronous cell divisions in the early C. elegans embryo.

Peres TV et al. (2016) BMC Pharmacol Toxicol ""Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies"."

Peres TV, Schettinger MR, Aschner M, Carvalho F, Bowman AB, Chen P, Avila DS

[BMC Pharmacol Toxicol, 2016]

Manganese (Mn) is an essential heavy metal. However, Mn's nutritional aspects are paralleled by its role as a neurotoxicant upon excessive exposure. In this review, we covered recent advances in identifying mechanisms of Mn uptake and its molecular actions in the brain as well as promising neuroprotective strategies. The authors focused on reporting findings regarding Mn transport mechanisms, Mn effects on cholinergic system, behavioral alterations induced by Mn exposure and studies of neuroprotective strategies against Mn intoxication. We report that exposure to Mn may arise from environmental sources, occupational settings, food, total parenteral nutrition (TPN), methcathinone drug abuse or even genetic factors, such as mutation in the transporter SLC30A10. Accumulation of Mn occurs mainly in the basal ganglia and leads to a syndrome called manganism, whose symptoms of cognitive dysfunction and motor impairment resemble Parkinson's disease (PD). Various neurotransmitter systems may be impaired due to Mn, especially dopaminergic, but also cholinergic and GABAergic. Several proteins have been identified to transport Mn, including divalent metal tranporter-1 (DMT-1), SLC30A10, transferrin and ferroportin and allow its accumulation in the central nervous system. Parallel to identification of Mn neurotoxic properties, neuroprotective strategies have been reported, and these include endogenous antioxidants (for instance, vitamin E), plant extracts (complex mixtures containing polyphenols and non-characterized components), iron chelating agents, precursors of glutathione (GSH), and synthetic compounds that can experimentally afford protection against Mn-induced neurotoxicity.

Martins AC et al. (2022) Biomolecules "Caenorhabditis elegans as a Model to Study Manganese-Induced Neurotoxicity."

Bornhorst J, Aschner M, Nicolai MM, Martins AC, Ke T, Li J, Moura AV, Gubert P, Bowman AB

[Biomolecules, 2022]

Caenorhabditis elegans (C. elegans) is a nematode present worldwide. The worm shows homology to mammalian systems and expresses approximately 40% of human disease-related genes. Since Dr. Sydney Brenner first proposed C. elegans as an advantageous experimental worm-model system for genetic approaches, increasing numbers of studies using C. elegans as a tool to investigate topics in several fields of biochemistry, neuroscience, pharmacology, and toxicology have been performed. In this regard, C. elegans has been used to characterize the molecular mechanisms and affected pathways caused by metals that lead to neurotoxicity, as well as the pathophysiological interrelationship between metal exposure and ongoing neurodegenerative disorders. Several toxic metals, such as lead, cadmium, and mercury, are recognized as important environmental contaminants, and their exposure is associated with toxic effects on the human body. Essential elements that are required to maintain cellular homeostasis and normal physiological functions may also be toxic when accumulated at higher concentrations. For instance, manganese (Mn) is a trace essential element that participates in numerous biological processes, such as enzymatic activities, energy metabolism, and maintenance of cell functions. However, Mn overexposure is associated with behavioral changes in C. elegans, which are consistent with the dopaminergic system being the primary target of Mn neurotoxicity. Caenorhabditis elegans has been shown to be an important tool that allows for studies on neuron morphology using fluorescent transgenic worms. Moreover, behavioral tests may be conducted using worms, and neurotransmitter determination and related gene expression are likely to change after Mn exposure. Likewise, mutant worms may be used to study molecular mechanisms in Mn toxicity, as well as the expression of proteins responsible for the biosynthesis, transport, storage, and uptake of dopamine. Furthermore, this review highlights some advantages and limitations of using the experimental model of C. elegans and provides guidance for potential future applications of this model in studies directed toward assessing for Mn neurotoxicity and related mechanisms.

Martins AC et al. (2023) Cells "Mitochondria in the Spotlight: C. elegans as a Model Organism to Evaluate Xenobiotic-Induced Dysfunction."

Rocha JBT, Aschner M, Virgolini MB, Avila DS, Martins AC, Skalny AV, Scharf P, Li J, Tinkov AA, Bowman AB

[Cells, 2023]

Mitochondria play a crucial role in cellular respiration, ATP production, and the regulation of various cellular processes. Mitochondrial dysfunctions have been directly linked to pathophysiological conditions, making them a significant target of interest in toxicological research. In recent years, there has been a growing need to understand the intricate effects of xenobiotics on human health, necessitating the use of effective scientific research tools. <i>Caenorhabditis elegans</i> (<i>C. elegans</i>), a nonpathogenic nematode, has emerged as a powerful tool for investigating toxic mechanisms and mitochondrial dysfunction. With remarkable genetic homology to mammals, <i>C. elegans</i> has been used in studies to elucidate the impact of contaminants and drugs on mitochondrial function. This review focuses on the effects of several toxic metals and metalloids, drugs of abuse and pesticides on mitochondria, highlighting the utility of <i>C. elegans</i> as a model organism to investigate mitochondrial dysfunction induced by xenobiotics. Mitochondrial structure, function, and dynamics are discussed, emphasizing their essential role in cellular viability and the regulation of processes such as autophagy, apoptosis, and calcium homeostasis. Additionally, specific toxins and toxicants, such as arsenic, cadmium, and manganese are examined in the context of their impact on mitochondrial function and the utility of <i>C. elegans</i> in elucidating the underlying mechanisms. Furthermore, we demonstrate the utilization of <i>C. elegans</i> as an experimental model providing a promising platform for investigating the intricate relationships between xenobiotics and mitochondrial dysfunction. This knowledge could contribute to the development of strategies to mitigate the adverse effects of contaminants and drugs of abuse, ultimately enhancing our understanding of these complex processes and promoting human health.

Soares ATG et al. (2020) J Trace Elem Med Biol "The impact of manganese on neurotransmitter systems."

Khan H, Santamaria A, Tinkov AA, Soares ATG, Bowman AB, Skalny AV, Skalnaya MG, Avila DS, Silva AC, Tsatsakis A, Aschner M

[J Trace Elem Med Biol, 2020]

BACKGROUND: Manganese (Mn) is a metal ubiquitously present in nature and essential for many living organisms. As a trace element, it is required in small amounts for the proper functioning of several important enzymes, and reports of Mn deficiency are indeed rare. METHODS: This mini-review will cover aspects of Mn toxicokinetics and its impact on brain neurotransmission, as well as its Janus-faced effects on humans and other animal's health. RESULTS: The estimated safe upper limit of intracellular Mn for physiological function is in anarrow range of 20-53M.Therefore, intake of higher levels of Mn and the outcomes, especially to the nervous system, have been well documented. CONCLUSION: The metal affects mostly the brain by accumulating in specific areas, altering cognitive functions and locomotion, thus severely impacting the health of the exposed organisms.

Pierre Gonczy (2005) WormBook "Asymmetric cell division and axis formation in the embryo."

Pierre Gonczy

[WormBook, 2005]

Asymmetric cell divisions play an important role in generating diversity during metazoan development. In the early C. elegans embryo, a series of asymmetric divisions are crucial for establishing the three principal axes of the body plan (AP, DV, LR) and for segregating determinants that specify cell fates. In this review, we focus on events in the one-cell embryo that result in the establishment of the AP axis and the first asymmetric division. We first describe how the sperm-derived centrosome initiates movements of the cortical actomyosin network that result in the polarized distribution of PAR proteins. We then briefly discuss how components acting downstream of the PAR proteins mediate unequal segregation of cell fate determinants to the anterior blastomere AB and the posterior blastomere P 1 . We also review how a heterotrimeric G protein pathway generates cortically based pulling forces acting on astral microtubules, thus mediating centrosome and spindle positioning in response to AP polarity cues. In addition, we briefly highlight events involved in establishing the DV and LR axes. The DV axis is established at the four-cell stage, following specific cell-cell interactions that occur between P 2 and EMS , the two daughters of P 1 , as well as between P 2 and ABp , a daughter of AB . The LR axis is established shortly thereafter by the division pattern of ABa and ABp . We conclude by mentioning how findings made in early C. elegans embryos are relevant to understanding asymmetric cell division and pattern formation across metazoan evolution.

Lublin AL et al. (2013) Drug Discov Today Technol "Alzheimer's disease drug discovery: in vivo screening using Caenorhabditis elegans as a model for beta-amyloid peptide-induced toxicity."

Link CD, Lublin AL

[Drug Discov Today Technol, 2013]

Alzheimer's disease (AD) is a complex human neurodegenerative disease. Currently the therapeutics for AD only treats the symptoms. While numbers of excellent studies have used mammalian models to discover new compounds, the time and effort involved with screening large numbers of candidates is prohibitive. Cultured mammalian neurons are often used to perform high-throughput screens (HTS); however, cell culture lacks the organismal complexity involved in AD. To address these issues several researchers are turning to the roundworm, Caenorhabditis elegans. C. elegans has numerous models of both Tau and Ab induced toxicity, the two prime components observed to correlate with AD pathology. These models have led to the discovery of numerous AD modulating candidates. Further, the ease of performing RNA interference for any gene in the C. elegans genome allows for identification of proteins involved in the mechanism of drug action. These attributes make C. elegans well positioned to aid in the discovery of new AD therapies.

Spieth J et al. (2014) WormBook "Overview of gene structure in C. elegans."

Lawson D, Howe K, Spieth J, Davis P, Williams G

[WormBook, 2014]

In the early stage of the C. elegans sequencing project, the ab initio gene prediction program Genefinder was used to find protein-coding genes. Subsequently, protein-coding genes structures have been actively curated by WormBase using evidence from all available data sources. Most coding loci were identified by the Genefinder program, but the process of gene curation results in a continual refinement of the details of gene structure, involving the correction and confirmation of intron splice sites, the addition of alternate splicing forms, the merging and splitting of incorrect predictions, and the creation and extension of 5' and 3' ends. The development of new technologies results in the availability of further data sources, and these are incorporated into the evidence used to support the curated structures. Non-coding genes are more difficult to curate using this methodology, and so the structures for most of these have been imported from the literature or from specialist databases of ncRNA data. This article describes the structure and curation of transcribed regions of genes.

Danielson PB (2002) Curr Drug Metab "The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans."

Danielson PB

[Curr Drug Metab, 2002]

Cytochrome p450s comprise a superfamily of heme-thiolate proteins named for the spectral absorbance peak of their carbon-monoxide-bound species at 450 nm. Having been found in every class of organism, including Archaea, the p450 superfamily is believed to have originated from an ancestral gene that existed over 3 billion years ago. Repeated gene duplications have subsequently given rise to one of the largest of multigene families. These enzymes are notable both for the diversity of reactions that they catalyze and the range of chemically dissimilar substrates upon which they act. Cytochrome p450s support the oxidative, peroxidative and reductive metabolism of such endogenous and xenobiotic substrates as environmental pollutants, agrochemicals, plant allelochemicals, steroids, prostaglandins and fatty acids. In humans, cytochrome p450s are best know for their central role in phase I drug metabolism where they are of critical importance to two of the most significant problems in clinical pharmacology: drug interactions and interindividual variability in drug metabolism. Recent advances in our understanding of cytochrome p450-mediated drug metabolism have been accelerated as a result of an increasing emphasis on functional genomic approaches to p450 research. While human cytochrome p450 databases have swelled with a flood of new human sequence variants, however, the functional characterization of the corresponding gene products has not kept pace. In response researchers have begun to apply the tools of proteomics as well as homology-based and ab initio modeling to salient questions of cytochrome p450 structure/function. This review examines the latest advances in our understanding of human cytochrome p450s.

Strome S (1989) Int Rev Cytol "Generation of cell diversity during early embryogenesis in the nematode Caenorhabditis elegans."

Strome S

[Int Rev Cytol, 1989]

Caenorhabditis elegans zygotes undergo a series of four differentiative divisions to generate 5 somatic founder cells and a germ-line progenitor cell by the 16- to 24-cell stage of embryogenesis. The pattern of divisions, cell positions, and development of the embryonic cells are invariant from embryo to embryo. Through a combination of embryo manipulation, treatment of embryos with pharmacologic agents, and genetic analysis of maternal-effect embryonic-lethal mutants, researchers in several laboratories have investigated when and how cell differences are generated and cell fates are specified during embryogenesis: 1. Most blastomeres develop in a cell-autonomous manner. They do not need to undergo cell division and they do not require their normal neighbors to express differentiation products characteristic of their lineage. In embryos in which specific cells have been ablated, the fates of neighboring cells do not change to compensate for the missing cells. These observations suggest that most embryonic cells are determined by lineally transmitted internally segregated information. 2. There is at least one clear-cut example of inductive interactions during early development. The anterior daughter of AB gives rise to hypodermis, neurons, pharyngeal muscles, and body wall muscles. Interactions between ABa cells and P1-derived blastomeres are required between the 4- and 28-cell stage for ABa to generate pharyngeal and body wall muscles. ABa appears to be directed to generate hypodermis by internally segregated cues and directed to generate muscle by external cues. 3. Certain of the early internal segregation events require the participation of microfilaments. Disruption of the microfilament array leads to the missegregation of germ granules and of the potential of cells to undergo unequal germ-line-like divisions. Microfilaments may be involved in many other segregation events as well. 4. Several maternal-effect lethal mutants also perturb zygotic segregation events. These par mutants, which divide symmetrically and fail to segregate germ granules, may identify genes whose products interact with microfilaments or otherwise participate in cytoplasmic localization during the early divisions.