Title: Gender Differences in the Renal Toxicity of the Neurotoxin Domoic Acid Griffin Thompson, Hernan Grenett, Lan He, Noor Alsirafi, Amanda Hanninen, and P. Darwin Bell University of Alabama Birmingham, and Birmingham VA, Birmingham, AL
Abstract:The algae‐derived neurotoxin, domoic acid (DA), is an ionotropic receptor agonist and is currently considered an increasing threat to mammals and other species. Intraperitoneal administration (IP) of ...The algae‐derived neurotoxin, domoic acid (DA), is an ionotropic receptor agonist and is currently considered an increasing threat to mammals and other species. Intraperitoneal administration (IP) of 4–5 mg/KgBW in mice has been found to cause neurological symptoms\damage. However, we recently reported (JASN 2104) that the kidney was 100 times more susceptible to injury with DA compared to brain. With IP injection, the kidney has a 4‐fold higher concentration of DA compared to brain and prior probenecid treatment leads to even further accumulations of DA suggesting that DA is secreted by the kidney. The purpose of these studies was to determine if there is a gender difference in the renal injury response to DA. Doses of 0.05 mg/Kg and 0.005 mg/Kg were IP injected into C57BL6 mice and 30 mins later the early injury‐response genes c‐fos, Junb, and EGR‐1were assessed using quantitative RT‐PCR. At this early time point both male and female mice exhibited an increase in gene expression. Surprisingly, female mice expression of early response genes was significantly higher, by approximately 2 fold, compared to male mice. Further studies were performed by implanting osmotic minipumps and infusing DA at a rate of 0.005 mg/KgBW per 24 hrs for 7 days. Urine DA levels were measured during this time by mass spectrometry. Over this period of time female mice excreted 50% less DA compared to male mice. Since the renal elimination of DA is both through both filtration and secretion, this suggests that female mice may have a reduced capacity to secrete DA. Our studies demonstrate that female mice are more susceptible to acute renal injury which maybe due to a reduced capability to excrete DA compared to male mice.Read More