Citation:

Oshiro, W., K. McDaniel, T. Beasley, G. Moser, AND D. Herr. Impacts of a perinatal exposure to manganese coupled with maternal stress in rats: Learning, memory and attentional function in exposed offspring. NEUROTOXICOLOGY AND TERATOLOGY. Elsevier Science Ltd, New York, NY, 91(May-June 2022):107077, (2022). https://doi.org/10.1016/j.ntt.2022.107077

Impact/Purpose:

The developmental effects of chemicals that co-occur in vulnerable populations with elevated physical and psychological stress is of increasing concern in risk assessment and a focus of research being conducted under Sustainable and Healthy Communities task (SHC 2.63). In both humans and animals, heightened stress during pregnancy can cause an increase in the circulating stress hormones in the mother. If this increase is persistent and occurs at critical timepoints during fetal brain development, it can result in altered neurodevelopment in offspring. Less is known about how these biological changes interact with effects of chemical exposures. To assess causality of these factors we developed a rodent model of co-occurring perinatal manipulations and conducted a series of behavioral and cognitive assessments in the offspring from birth through adulthood. Manganese (Mn), a potential neurodevelopmental toxicant of Agency concern, was delivered in drinking water (0, 2, or 4 mg/ml Mn) of pregnant rats from gestational day (GD) 7 to postnatal day (PND22). A variable stress paradigm designed to psychologically challenge the dams was applied to half of the animals from GD13 to PND9.  This developmental period in the rat corresponds to development of the hippocampal pyramidal cells, cerebral cortex, and hypothalamus, which are of primary areas of interest to us since they mediate spatial learning and memory, executive order functions, memory, and the hypothalamic-pituitary-adrenal (HPA) axis.  Here we report results of cognitive assessments conducted in exposed adolescent and adult offspring. Perinatal stress and Mn exposure both affected overlapping cognitive indices including learning, memory, and attentional processes. These effects were often gender-dependent and included bi-directional changes in these indices often dependent on the Mn dose and the task parameters. Combined these two factors did not exacerbate these effects, but often attenuated the effects and reduced the gender-specificity of the effects. Still, the effects of perinatal stress alone on these cognitive functions may undermine the detection of effects due to chemical exposure and underscores the need to consider the psychological health and wellbeing of the mother and her environment in risk assessment of developmental neurotoxicants.

Description:

The developmental effects of chemicals that co-occur in vulnerable populations with elevated psychological stress are of increasing concern to the public. To investigate these concerns, we developed a rodent model of co-occurring perinatal manipulations and conducted a series of cognitive assessments in male and female offspring. Manganese (Mn), a neurodevelopmental toxicant when exceeding physiological requirements, was delivered in the drinking water (0, 2, or 4 mg Mn/mL) of pregnant rats from gestational day (GD) 7 to postnatal day (PND) 22. A variable perinatal stress paradigm was applied to half of the animals from GD13 to PND9. Novel object recognition (NOR), Morris water maze (MWM), differential reinforcement of low-rates procedure (DRL), cued and uncued choice reaction time (CRT) tests were used to assess cognitive functions in offspring. Mn (4 mg/mL) and stress impaired NOR in adolescent males but facilitated NOR performance in females. However, when stress and Mn were combined these effects were attenuated in both sexes. During training for the DRL, Mn (2 mg/mL) facilitated, while stress impaired, lever press learning in both genders. Few treatment effects were found on DRL or MWM performances.  During the CRT evaluations, Mn (2 and 4 mg/mL) and stress reduced cued attention in males, while stress reduced uncued attention in females. Mn and stress increased anticipatory responding in cued CRT in both genders, while only stress affected this measure in females during uncued CRT. Mn and stress slowed decision time in both sexes and in both CRT tests, while movement time was slowed by stress in females. For all CRT measures Mn combined with stress either eliminated the gender-specific differences and attenuated or improved the responses observed with either factor alone, depending on the concentration of Mn. The effects of perinatal stress on these cognitive functions may undermine the detection of effects due to chemical exposure and underscores the need to consider the psychological health and wellbeing of the mother and her environment in risk assessment for developmental neurotoxicity of chemicals.

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