James M. Donald

Neurobehavioral effects in offspring of mice given excess aluminum in diet during gestation and lactation

Aluminum (Al) as Al lactate in a purified diet (25, 500 or 1000 micrograms Al/g diet) was fed to Swiss-Webster mice from conception through weaning. Weights, food intake and toxic signs were recorded at regular intervals and pregnancy outcome evaluated. Pups were assessed for growth, neurobehavioral development and toxic signs prior to weaning. Offspring were also evaluated with a multi-item neurobehavioral test battery immediately after weaning and again after a 2-week period during which they were all fed control (25 micrograms/g Al) diet. No maternal or reproductive toxicity was detected and there were no group differences in pup mortality, growth, toxic signs, or neurobehavioral development prior to weaning, with the exception of poor performance in a climbing test in the 1000 micrograms Al/g diet group. Parameters significantly affected by Al in the postweaning neurobehavioral testing were foot splay, forelimb and hindlimb grip strengths, and thermal sensitivity. Negative geotaxis was inconsistently affected and startle responses were not affected. These results show that maternal dietary exposure to excess Al during gestation and lactation which do not produce maternal toxicity can result in persistent neurobehavioral deficits in weanling mice.

Bisphenol A: developmental toxicity from early prenatal exposurea

Bisphenol A (BPA) exposure has been documented in pregnant women, but consequences for development are not yet widely studied in human populations. This review presents research on the consequences for offspring of BPA exposure during pregnancy. Extensive work in laboratory rodents has evaluated survival and growth of the conceptus, interference with embryonic programs of development, morphological sex differentiation, sex differentiation of the brain and behavior, immune responsiveness, and mechanism of action. Sensitive measures include RAR, aryl hydrocarbon receptor, and Hox A10 gene expression, anogenital distance, sex differentiation of affective and exploratory behavior, and immune hyperresponsiveness. Many BPA effects are reported at low doses (10-50 µg/kg d range) by the oral route of administration. At high doses (>500,000 µg/kg d) fetal viability is compromised. Much of the work has centered around the implications of the estrogenic actions of this agent. Some work related to thyroid mechanism of action has also been explored. BPA research has actively integrated current knowledge of developmental biology, concepts of endocrine disruption, and toxicological research to provide a basis for human health risk assessment.

Maternal and developmental toxicity of chronic aluminum exposure in mice

The present study demonstrated aluminum-induced neurotoxicity in mouse dams and developmental retardation in their offspring following oral exposure to several dose levels during gestation and lactation. Female mice fed aluminum lactate (AL) at levels of 500 or 1000 ppm in their diet from Day 0 gestation to Day 21 postpartum were compared to mice which received a 100 ppm aluminum diet either ad libitum or pair-fed to the 1000 ppm AL group. Dams receiving the 500 and 1000 ppm AL diets showed signs of neurotoxicity beginning at Days 12-15 postpartum and showed significant weight loss. Offspring showed dose-dependent decreases in body weight (F = 6.47, p less than 0.001), crown-rump length (F = 7.37, p less than 0.0001), and ponderal index (F = 6.90, p less than 0.0002), at birth and preweaning. Absolute and relative liver and spleen weights were lower in pups from the high AL groups compared to controls (F = 3.34, p less than 0.025 and F = 15.54, p less than 0.001, respectively). Neurobehavioral development was somewhat delayed in aluminum-treated pups, but not in their pair-fed controls (F = 5.52, p less than 0.005). In addition to showing oral toxicity of excess AL during development dose-dependent toxic effects of parenteral aluminum exposure were demonstrated in pregnant mice which were injected subcutaneously with aluminum lactate solution at 10, 20, or 40 mg Al/kg body wt on Days 3, 5, 7, 9, 12, 13, and 15 of gestation. Maternal spleen and liver weights were significantly increased in aluminum treated animals (p less than 0.001 and p less than 0.05, respectively). Fetal crown-rump lengths were significantly reduced in the 20 mg/kg aluminum group (F = 9.79, p less than 0.001).

Reduced water intake: Implications for rodent developmental and reproductive toxicity studies†

In developmental and reproductive toxicity studies, drinking water is a common means of delivering the test agent. Reduced consumption of toxicant-containing water raises questions about indirect effects of reduced maternal fluid consumption resulting from unpalatability, versus direct effects of the test compound. Issues to consider include: objective assessment of dehydration and thirst, the relative contributions of innate and learned behaviors to drinking behavior and flavor preference, and the objective assessment of physiologic stress. Not only do lab animals under ad lib conditions consume more water than the minimum required to maintain fluid balance, animals faced with water restriction have substantial physiologic capacity for protection of metabolic processes. Measures of blood biochemistry can provide quantifiable, objective indications of fluid balance, but changes in these parameters could result from other causes such as effects of a test toxicant. Consummatory behaviors in response to perceived need are highly influenced by learning. Hence, the drinking behavior, water intake, and flavor acceptance/preference of animals used in toxicology experiments could be subject to learning experiences with the test compound. Physiological symptoms of stress produced by water deprivation may be distinguishable from the symptoms associated with other generalized stressors, such as food deprivation, but doing so may be beyond the scope of most developmental or reproductive toxicity studies. Use of concurrent controls, paired to test groups for water consumption, could help distinguish between the direct effects of a test toxicant as opposed to effects of reduced water consumption alone.