Chronic, low-level oral exposure to marine toxin, domoic acid, alters whole brain morphometry in nonhuman primates

Petroff, Rebekah; Richards, Todd L.; Crouthamel, Brenda; McKain, Noelle; Stanley, Courtney; Grant, Kimberly S.; Shum, Sara; Jing, Jing; Isoherranen, Nina; Burbacher, Thomas M.

doi:10.1016/j.neuro.2019.02.016

Cited by 25 publications

(14 citation statements)

References 70 publications

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“…The data from this study show the reduction in the degree of differentiation of rNSC into all three type of cells and the reduction in axonal length of neurons in the presence of low non-cytotoxic concentration of DA (0.05 μM). Data from rodents and non-human primates have shown that non-cytotoxic low dose exposure to DA during early life was associated with behavioral, memory deficits, and/or structural changes in the brain [47,48,49,50,51,52]. This memory loss may be linked to a reduction and/or the abnormal differentiation of neural stem cells.…”

Section: Discussionmentioning

confidence: 99%

Detecting Neurodevelopmental Toxicity of Domoic Acid and Ochratoxin A Using Rat Fetal Neural Stem Cells

Gill

Kumara

2019

Marine Drugs

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Currently, animal experiments in rodents are the gold standard for developmental neurotoxicity (DNT) investigations; however, testing guidelines for these experiments are insufficient in terms of animal use, time, and costs. Thus, alternative reliable approaches are needed for predicting DNT. We chose rat neural stem cells (rNSC) as a model system, and used a well-known neurotoxin, domoic acid (DA), as a model test chemical to validate the assay. This assay was used to investigate the potential neurotoxic effects of Ochratoxin A (OTA), of which the main target organ is the kidney. However, limited information is available regarding its neurotoxic effects. The effects of DA and OTA on the cytotoxicity and on the degree of differentiation of rat rNSC into astrocytes, neurons, and oligodendrocytes were monitored using cell-specific immunofluorescence staining for undifferentiated rNSC (nestin), neurospheres (nestin and A2B5), neurons (MAP2 clone M13, MAP2 clone AP18, and Doublecortin), astrocytes (GFAP), and oligodendrocytes (A2B5 and mGalc). In the absence of any chemical exposure, approximately 46% of rNSC differentiated into astrocytes and neurons, while 40% of the rNSC differentiated into oligodendrocytes. Both non-cytotoxic and cytotoxic concentrations of DA and OTA reduced the differentiation of rNSC into astrocytes, neurons, and oligodendrocytes. Furthermore, a non-cytotoxic nanomolar (0.05 µM) concentration of DA and 0.2 µM of OTA reduced the percentage differentiation of rNSC into astrocytes and neurons. Morphometric analysis showed that the highest concentration (10 μM) of DA reduced axonal length. These indicate that low, non-cytotoxic concentrations of DA and OTA can interfere with the differentiation of rNSC.

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Section: Discussionmentioning

confidence: 99%

Detecting Neurodevelopmental Toxicity of Domoic Acid and Ochratoxin A Using Rat Fetal Neural Stem Cells

Gill

Kumara

2019

Marine Drugs

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“…Such a pattern has been observed previously in human patients with mTLE (Concha et al ., 2010; Dinkelacker et al ., 2015; Otte et al ., 2012). Diffusion MRI has also been used to study chronic, low-level DOM exposure in live macaques (Petroff et al 2019), and preliminary evidence indicates altered white matter parameters in the fornix as well as the internal capsule.…”

Section: Methodsmentioning

confidence: 99%

“…Ongoing studies with laboratory primates suggest delayed developmental effects occur in primates exposed in utero , but these findings will take several years to confirm, and due to expense, are of limited sample sizes (Burbacher et al . 2019, Petroff et al . 2019).…”

Section: Introductionmentioning

confidence: 99%

An MRI protocol for anatomical and functional evaluation of the California sea lion brain

Cook

Hoard

Dolui

et al. 2020

Preprint

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We describe a research MRI protocol for in vivo evaluation of pinniped brains using standard human clinical MRI hardware and pulse sequences. Our intended application is to study development of California sea lions (Zalophus californianus) exposed in utero to domoic acid (DOM) produced by harmful algae blooms in the coastal Pacific Ocean. In cases where the fetus survives to birth, exposure to the toxin in utero could result in developmental abnormalities leading to neurological and behavioral deficits. Prior studies on sea lions naturally exposed to DOM as adults have demonstrated hippocampal atrophy and altered mesial temporal connectivity. This MRI protocol is therefore intended to depict the hippocampal formation as the primary region of interest, and to provide longitudinal measures of brain functional and structural connectivity as well as quantitative anatomical evaluations. Scan quality and utility are assessed by comparison with prior studies in live and post mortem sea lion brains. We include the first determination of cerebral blood flow mapping using MRI, and also the first fiber tractography using diffusion-weighted imaging from a live sea lion brain. The protocol also facilitates screening for common neurological pathologies, including tumors, trauma and hemorrhages. We believe the protocol would be suitable for any pinniped that can fit inside a human MRI scanner.

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“…Adult humans acutely exposed to DomA developed sensorimotor neuropathy and axonopathy as assessed by electromyography (Teitelbaum et al, 1990). A subset of primates exposed orally at or near the accepted daily tolerable dose of 0.075 mg/kg developed visible hand tremors (Petroff et al, 2019). Rodents prenatally exposed to DomA (PND 10-17) developed aberrant gait patterns (Shiotani et al, 2017).…”

Section: Implications For Human Healthmentioning

confidence: 99%

Developmental exposure to domoic acid disrupts startle response behavior and circuitry

Panlilio

Jones

Salanga

et al. 2021

Preprint

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Harmful algal blooms produce potent neurotoxins that accumulate in seafood and are hazardous to human health. Developmental exposure to the harmful algal bloom toxin, domoic acid (DomA), has behavioral consequences well into adulthood, but the cellular and molecular mechanisms are largely unknown. To assess these, we exposed zebrafish embryos to DomA during the previously identified window of susceptibility (2 days post-fertilization) and used the well-known startle response circuit as a tool to identify specific neuronal components that are targeted by exposure to DomA. Exposure to DomA reduced the probability of eliciting a startle after auditory/vibrational or electrical stimuli and led to the dramatic reduction of one type of startle, short latency c-start (SLC) responses. Furthermore, DomA-exposed larvae had altered kinematics of both SLC and long latency c-start (LLC) startle responses, exhibiting shallower bend angles and slower maximal angular velocities. Using vital dye staining, immunolabelling, and live imaging of transgenic lines, we determined that while the sensory inputs were intact, the reticulospinal neurons required for SLC responses were absent in most DomA-exposed larvae. Furthermore, axon tracing revealed that DomA-treated larvae also showed significantly reduced primary motor neuron axon collaterals. Overall, these results show that developmental exposure to DomA leads to startle deficits by targeting specific subsets of neurons. These findings provide mechanistic insights into the neurodevelopmental effects of excess glutamatergic signaling caused by exposure to DomA. It further provides a model for using the startle response circuit to identify neuronal populations targeted by toxin or toxicant exposures.Summary statementWe used the zebrafish startle response as a tool to identify sensory-motor deficits and the loss of specific neural populations after developmental exposure to the harmful algal bloom toxin domoic acid.GRAPHICAL ABSTRACT

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Chronic, low-level oral exposure to marine toxin, domoic acid, alters whole brain morphometry in nonhuman primates

Cited by 25 publications

References 70 publications

Detecting Neurodevelopmental Toxicity of Domoic Acid and Ochratoxin A Using Rat Fetal Neural Stem Cells

Detecting Neurodevelopmental Toxicity of Domoic Acid and Ochratoxin A Using Rat Fetal Neural Stem Cells

An MRI protocol for anatomical and functional evaluation of the California sea lion brain

Developmental exposure to domoic acid disrupts startle response behavior and circuitry

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