Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS

Abstract

Domoic acid is an algal-derived seafood toxin that functions as a glutamate agonist and exerts excitotoxicity via overstimulation of glutamate receptors (AMPA, NMDA) in the central nervous system (CNS). At high (symptomatic) doses, domoic acid is well-known to cause seizures, brain lesions and memory loss; however, a significant knowledge gap exists regarding the health impacts of repeated low-level (asymptomatic) exposure. Here, we investigated the impacts of low-level repetitive domoic acid exposure on gene transcription and mitochondrial function in the vertebrate CNS using a zebrafish model in order to: 1) identify transcriptional biomarkers of exposure; and 2) examine potential pathophysiology that may occur in the absence of overt excitotoxic symptoms. We found that transcription of genes related to neurological function and development were significantly altered, and that asymptomatic exposure impaired mitochondrial function. Interestingly, the transcriptome response was highly-variable across the exposure duration (36 weeks), with little to no overlap of specific genes across the six exposure time points (2, 6, 12, 18, 24, and 36 weeks). Moreover, there were no apparent similarities at any time point with the gene transcriptome profile exhibited by the glud1 mouse model of chronic moderate excess glutamate release. These results suggest that although the fundamental mechanisms of toxicity may be similar, gene transcriptome responses to domoic acid exposure do not extrapolate well between different exposure durations. However, the observed impairment of mitochondrial function based on respiration rates and mitochondrial protein content suggests that repetitive low-level exposure does have fundamental cellular level impacts that could contribute to chronic health consequences.

Chronic low-level exposure to the common seafood toxin domoic acid causes cognitive deficits in mice

“…The effects of chronic low-level asymptomatic exposure have not been well studied and are of particular concern for coastal communities including recreational and Tribal harvesters who regularly consume shellfish such as razor clams that are known to retain low levels of DA in edible tissues for more than a year after HAB events (Lefebvre and Robertson, 2010; Wekell et al, 1994). In a study with long-term whole animal exposures to low asymptomatic doses of DA, zebrafish ( Danio rerio ) had altered gene transcriptomes and impaired mitochondrial function in whole brains after nine months of weekly exposures (Hiolski et al, 2014). Additionally, chronic low-level exposure did not confer resistance to DA, but instead increased toxin sensitivity making the neurologic effects of subsequent exposures more pronounced in chronically exposed animals (Hiolski et al, 2014).…”

Acute and chronic dietary exposure to domoic acid in recreational harvesters: A survey of shellfish consumption behavior

“…Limited studies have shown the potential for human health impacts from chronic, low level DA exposure. Repetitive, low dose experiments simulating chronic exposure have shown increased toxin susceptibility and impaired mitochondrial function in zebrafish after 20 weeks and 18 weeks respectively (Hiolski et al 2014; Lefebvre et al 2012). Truelove et al (1996) and Truelove et al (1997) found no signs of toxicity after repeated, low dose DA exposure in cynomolgus monkeys (30 day exposure) and rats (64 day exposure), although these studies focused on traditional clinical indicators of toxicity such as gross histologic lesions and blood chemistry.…”

“…Chronic low level DA exposure (i.e. levels below those that cause the overt signs of toxicity listed above) has been connected to increased toxin susceptibility and impaired mitochondrial function in laboratory studies, and potential memory deficits in humans (Grattan et al 2016; Hiolski et al 2014; Lefebvre et al 2012). …”

“…California sea lions ( Zalophus californianus ) and rats have shown chronic health effects in the form of persistent toxicity syndrome stemming from short-term, acute DA exposure (Cook et al 2015; Goldstein et al 2008; Muha and Ramsdell 2011). Repetitive (chronic), low-level DA exposure experiments have shown subclinical signs of toxicity in the form of increased toxin susceptibility and impaired mitochondrial function in zebrafish (Hiolski et al 2014; Lefebvre et al 2012) while shorter-term repetitive low-level exposure studies in rats and cynomolgus monkeys reported no signs of toxicity (Truelove et al 1996; Truelove et al 1997). Grattan et al (2016) were the first to study chronic DA exposure in human consumers (American Indians in Washington State), recording potential memory impairment associated with chronic, low level DA exposure via self-reported razor clam consumption.…”

An attempt to semi-quantify potentially toxic diatoms of the genus <i>Pseudo-nitzschia</i> in Tokyo Bay, Japan by using massively parallel sequencing technology

“…Consequently, exhaustive monitoring of Pseudo-nitzschia has not been carried out to date in Japanese coastal waters. More recent studies have indicated that chronic exposure to even low levels of DA in humans can cause negative effects at the cellular level, which may in turn cause chronic health problems (Hiolski et al 2014). Thus, monitoring programs that focus only on the detection of DA concentrations higher than the regulatory limit in shellfish do not guarantee the safety of food or the protection of human health.…”