Power spectrum analysis of EEG in a translational nonhuman primate model after chronic exposure to low levels of the common marine neurotoxin, domoic acid.

Domoic acid (DA), the focus of this research, is a marine algal neurotoxin and epileptogen produced by species in the genus Pseudo-nitzschia. DA is found in finfish and shellfish across the globe. The current regulatory limit for DA consumption (20 ppm in shellfish) was set to protect humans from acute toxic effects, but there is a growing body of evidence suggesting that regular consumption of DA contaminated seafood at or below the regulatory limit may lead to subtle neurological effects in adults. The present research uses a translational nonhuman primate model to assess neurophysiological changes after chronic exposure to DA near the regulatory limit. Sedated electroencephalography (EEG) was used in 20 healthy adult female Macaca fascicularis, orally administered 0.075 and 0.15 mg DA/kg/day for at least 10 months. Paired video and EEG recordings were cleaned and a Fast Fourier Transformation was applied to EEG recordings to assess power differences in frequency bands from 1-20 Hz. When DA exposed animals were compared to controls, power was significantly decreased in the delta band (1-4 Hz, p < 0.005) and significantly increased in the alpha band (5-8 Hz, p < 0.005), theta band (9-12 Hz, p < 0.01), and beta band (13-20 Hz, p < 0.05). The power differences were not dose dependent or related to the duration of DA exposure, or subtle clinical symptoms of DA exposure (intentional tremors). Alterations of power in these bands have been associated with a host of clinical symptoms, such as deficits in memory and neurodegenerative diseases, and ultimately provide new insight into the subclinical toxicity of chronic, low-dose DA exposure on the adult primate brain.

Nonhuman primates as animal models for toxicology research.

There is a long history for the use of nonhuman primates in toxicological research. This unit reviews applications in reproductive toxicology and teratology, neural toxicology and neurobehavioral toxicology, immunotoxicology, respiratory (lung) toxicology, and chemical carcinogenesis.

Methods for studying nonhuman primates in neurobehavioral toxicology and teratology.

The behavioral repertoire of nonhuman primates is highly evolved and includes advanced problem-solving capabilities, complex social relationships, and sensory acuity equal or superior to humans. These factors make nonhuman primates valuable animal models for studies of the functional effects of neurotoxicants. This review provides descriptions of tests designed to study learning, memory, schedule-controlled behavior, information processing, social behavior, sensory functioning, and visual-motor coordination and/or visuospatial orientation in macaque monkeys. Whenever possible, the results of studies in primate behavioral toxicology are provided for individual test measures. The primate model is especially useful for studies of developmental exposures because monkeys, like humans, have relatively prolonged periods of gestation, infancy, and adolescence. In recognition of this, a special section is provided for tasks that are specifically designed to study behavioral processes in infant monkeys.

Infant monkeys' visual responses to drawings of normal and distorted faces.

Face-like patterns attract attention from both human and nonhuman primates. The present study explored the facial preferences in infant pigtailed macaques (Macaca nemestrina). Twenty-five subjects looked at 20 paired drawings of adult conspecific monkey faces, and their looking time was recorded. The facial features in the drawings were arranged in positions ranging from a normal to a scrambled face. The subjects looked at the normal face more than expected by chance (P < .02), suggesting a preference, whereas the distorted faces were observed randomly. The normal face may have been preferred because the eyes were in a normal position within the facial outline.

The effect of low-level prenatal methylmercury exposure on visual recognition memory in infant crab-eating macaques.

Infant crab-eating macaques exposed in utero to maternal subclinical levels of methylmercury (MeHg) and their nonexposed controls were administered an adaptation of a standardized test of visual recognition memory. Exposed animals showed recognition deficits in that they directed significantly less visual attention to novel stimuli than did controls. These results parallel those obtained by other investigators with high-risk and teratogen-exposed human infants.

Methylmercury exposure and reproductive dysfunction in the nonhuman primate.

Macaca fascicularis females were monitored daily through four menstrual cycles then orally administered 0, 50, or 90 micrograms/kg/day methylmercury hydroxide (MeHg). Females were monitored through four additional menstrual cycles and after approximately 124 days of MeHg treatment were time-mated to nontreated males. MeHg treatment did not affect menstrual cycle or menses length. The relationship between dosage of MeHg and reproductive outcome approached but did not reach statistical significance. Reproductive failure (i.e., nonconception, abortion) was, however, related to a significantly higher blood Hg concentration than reproductive success for MeHg-treated females. The offspring of MeHg-treated females tended to be smaller than control infants, but no statistically significant decrease in gestation, birthweight, or crown-rump length was observed. None of the females receiving MeHg exhibited signs of MeHg toxicity during breeding or pregnancy. Daily treatment with 90 micrograms/kg/day MeHg for nearly 1 year, however, produced signs of toxicity in four of seven females. Toxicity was related to increased maternal size, duration of MeHg treatment, and a blood Hg concentration of 2.3 to 2.8 ppm.