Characterization of Renal Toxicity in Mice Administered the Marine Biotoxin Domoic Acid

Abstract

Domoic acid (DA), an excitatory amino acid produced by diatoms belonging to the genus Pseudo-nitzschia, is a glutamate analog responsible for the neurologic condition referred to as amnesic shellfish poisoning. To date, the renal effects of DA have been underappreciated, although renal filtration is the primary route of systemic elimination and the kidney expresses ionotropic glutamate receptors. To characterize the renal effects of DA, we administered either a neurotoxic dose of DA or doses below the recognized limit of toxicity to adult Sv128/Black Swiss mice. DA preferentially accumulated in the kidney and elicited marked renal vascular and tubular damage consistent with acute tubular necrosis, apoptosis, and renal tubular cell desquamation, with toxic vacuolization and mitochondrial swelling as hallmarks of the cellular damage. Doses$0.1 mg/kg DA elevated the renal injury biomarkers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, and doses$0.005 mg/kg induced the early response genes c-fos and junb. Coadministration of DA with the broad spectrum excitatory amino acid antagonist kynurenic acid inhibited induction of c-fos, junb, and neutrophil gelatinase-associated lipocalin. These findings suggest that the kidney may be susceptible to excitotoxic agonists, and renal effects should be considered when examining glutamate receptor activation. Additionally, these results indicate that DA is a potent nephrotoxicant, and potential renal toxicity may require consideration when determining safe levels for human exposure.

Biosynthesis of the neurotoxin domoic acid in a bloom-forming diatom

“…In humans, a high, single-exposure dose of DA can cause amnesic shellfish poisoning (ASP), which involves symptoms of amnesia, seizures, coma, and in extreme cases, death. Even chronic, low-level consumption of DA may lead to kidney damage, cognitive deficit, and impairment of fetal development, making DA outbreaks an important human health problem (7–10). Similar neurotoxic symptoms have been observed in birds and marine mammals such as sea lions, which suffer spatial memory impairment linked to DA consumption, likely leading to increases in sea lion strandings (11).…”

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

“…Elderly consumers had higher susceptibility to DA toxicity in the 1987 Canadian DA poisoning event summarized by Perl et al (1990) and aged rats have shown higher susceptibility to DA toxicity, potentially due to impaired renal function, increased blood-brain barrier permeability, or loss of intrinsic neuroprotective mechanisms during brain aging (Hesp et al 2007; Hesp et al 2004; Kerr et al 2002). Renal filtration is the primary route for DA elimination and impaired renal function can increase DA toxicity in mice and rats (Funk et al 2014; Suzuki and Hierlihy 1993). …”

“…The use of this consumption rate (6 clams·day −1 ) and a single body weight (70kg) for exposure calculations risks the omission of temporal, demographic, and spatial variation in toxin exposure found in other recreational fisheries (Burger and Gochfeld 2011; Gochfeld and Burger 2011; Marien 1996). Consumers who eat more than six clams in a meal, weigh less than 70 kg, or are otherwise sensitive to DA toxicity (children, pregnant women, elderly, and those with renal dysfunction) may not be adequately protected by current DA regulations (Doucette et al 2004; Doucette et al 2000; Funk et al 2014; Hesp et al 2007; Maucher and Ramsdell 2007; Perl et al 1990). …”

“…Limited studies on low dose, acute DA exposure and low dose, repetitive DA exposure present the potential for human health impacts that are not currently regulated. Lower dose, short-term DA exposures in mouse and rat models have led to lower seizure thresholds, persistent changes in behavioral and molecular indicators of stress response, renal dysfunction, and effects on levels of spontaneous behavior (Funk et al 2014; Gill et al 2010; Gill et al 2012; Schwarz et al 2014). 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).…”

Integrating scFv into xMAP Assays for the Detection of Marine Toxins

“…Besides typical food poisoning symptoms, short term memory loss, confusion, and disorientation are observed in ASP. Although higher levels of DA are needed for intoxication, it is a heat stable toxin that can cause kidney damage at levels several orders of magnitude lower than those that cause neurological symptoms [5,6]. It acts by stimulating the glutamate receptors.…”