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Early Developmental Low-Dose Methylmercury Exposure Alters Learning and Memory in Periadolescent but Not Young Adult Rats.

ABSTRACT: Few studies have assessed the effects of developmental methylmercury (MeHg) exposure on learning and memory at different ages. The possibility of the amelioration or worsening of the effects has not been sufficiently investigated. This study aimed to assess whether low-dose MeHg exposure in utero and during suckling induces differential disturbances in learning and memory of periadolescent and young adult rats. Four experimental groups of pregnant Sprague-Dawley rats were orally exposed to MeHg or vehicle from gestational day 5 to weaning: (1) control (vehicle), (2) 250??g/kg/day MeHg, (3) 500??g/kg/day MeHg, and (4) vehicle, and treated on the test day with MK-801 (0.15?mg/kg i.p.), an antagonist of the N-methyl D-aspartate receptor. The effects were evaluated in male offspring through the open field test, object recognition test, Morris water maze, and conditioned taste aversion. For each test and stage assessed, different groups of animals were used. MeHg exposure, in a dose-dependent manner, disrupted exploratory behaviour, recognition memory, spatial learning, and acquisition of aversive memories in periadolescent rats, but alterations were not observed in littermates tested in young adulthood. These results suggest that developmental low-dose exposure to MeHg induces age-dependent detrimental effects. The relevance of decreasing exposure to MeHg in humans remains to be determined.

SUBMITTER: Albores-Garcia D

PROVIDER: S-EPMC4738696 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Early Developmental Low-Dose Methylmercury Exposure Alters Learning and Memory in Periadolescent but Not Young Adult Rats.

Albores-Garcia Damaris D Acosta-Saavedra Leonor C LC Hernandez Alberto J AJ Loera Miriam J MJ Calderón-Aranda Emma S ES

BioMed research international 20160113

Few studies have assessed the effects of developmental methylmercury (MeHg) exposure on learning and memory at different ages. The possibility of the amelioration or worsening of the effects has not been sufficiently investigated. This study aimed to assess whether low-dose MeHg exposure in utero and during suckling induces differential disturbances in learning and memory of periadolescent and young adult rats. Four experimental groups of pregnant Sprague-Dawley rats were orally exposed to MeHg ...[more]

PMID: 26885512

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Project description:BackgroundExposure to the bioaccumulative pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) has been associated with increased risk of insulin resistance and obesity in humans and experimental animals. These effects appear to be mediated by reduced brown adipose tissue (BAT) thermogenesis, which is regulated by the sympathetic nervous system. Although the neurotoxicity of DDT is well-established, whether DDT alters sympathetic innervation of BAT is unknown. We hypothesized that perinatal exposure to DDT or DDE promotes thermogenic dysfunction by interfering with sympathetic regulation of BAT thermogenesis.MethodsPregnant C57BL/6 J mice were administered environmentally relevant concentrations of DDTs (p,p'-DDT and o,p'-DDT) or DDE (p,p'-DDE), 1.7 mg/kg and 1.31 mg/kg, respectively, from gestational day 11.5 to postnatal day 5 by oral gavage, and longitudinal body temperature was recorded in male and female offspring. At 4 months of age, metabolic parameters were measured in female offspring via indirect calorimetry with or without the β3 adrenergic receptor agonist, CL 316,243. Immunohistochemical and neurochemical analyses of sympathetic neurons innervating BAT were evaluated.ResultsWe observed persistent thermogenic impairment in adult female, but not male, mice perinatally exposed to DDTs or p,p'-DDE. Perinatal DDTs exposure significantly impaired metabolism in adult female mice, an effect rescued by treatment with CL 316,243 immediately prior to calorimetry experiments. Neither DDTs nor p,p'-DDE significantly altered BAT morphology or the concentrations of norepinephrine and its metabolite DHPG in the BAT of DDTs-exposed mice. However, quantitative immunohistochemistry revealed a 20% decrease in sympathetic axons innervating BAT in adult female mice perinatally exposed to DDTs, but not p,p'-DDE, and 48 and 43% fewer synapses in stellate ganglia of mice exposed to either DDTs or p,p'-DDE, respectively, compared to control.ConclusionsThese data demonstrate that perinatal exposure to DDTs or p,p'-DDE impairs thermogenesis by interfering with patterns of connectivity in sympathetic circuits that regulate BAT.

Project description:Three-month old zebrafish were fed Biodiet starter (4% body weight per day) with MeHg added at 0, 0.5, 5 and 50 ppm for six weeks. Atomic absorption spectrometry was applied to measure the level of MeHg in the whole fish body. Zebrafish at six weeks were sampled from each group for gene expression analysis by NimbleGen Gene Expression 12X135K zebrafish microarrays. MeHg-exposed trout and zebrafish did not show overt signs of toxicity, nor were significant differences seen in mortality, length, mass, or condition factor. The chronic accumulation of total Hg in zebrafish exhibited dose- and time-dependent patterns. The dysregulated genes in MeHg-treated fish have multiple functional annotations, such as involving metabolism, cellular development, ion binding, stress response, transcriptional regulation, and apoptotic pathways. These results show that numerous molecular pathways involved in the growth and development of multiple organ systems are disrupted by exposure to moderate levels of dietary MeHg. The dysregulated genes will be selected by further analysis and used as biomarkers for MeHg exposure in aquatic environments. This study will allow us to assess the potential impacts of low-level exposure to environmental MeHg in the food chain and on the health of humans and animals. Three-month old zebrafish (Danio rerio, average body 0.149 g) were fed Biodiet Starter (Bio-Oregon) 4% of body weight per day with MeHg added at 0ppm, 0.5ppm, 5ppm and 50ppm (with ethanol as vehicle). Fish at six weeks were sampled from each group for gene expression analysis. Three fish from each treatment group were used for microarray experiments. Total RNA from individual fish was isolated using Trizol reagent (Invitrogen) and further purified using the RNeasy MiniElute cleanup kit (Qiagen). Double-strand cDNA was synthesized from 10ug total RNA of individual fish by using Superscript Double-Stranded cDNA synthesis Kit (Invitrogen). ). One ug double strand DNA was labeled with Cy3 using One-Color DNA labeling Kit (NimbleGen), then hybridized to NimbleGen 12X135K array. The arrays were scanned at 2um on a NimbleGen MS200 scanner with auto-gain adjust. The TIFF images were gridded and extracted using NimbleScan v. 2.6. Expression data were normalized using the Robust Multichip Average (RMA) algorithm.

Project description:IntroductionEpisodic memory formation requires the binding of multiple associations to a coherent episodic representation, with rich detail of times, places, and contextual information. During postnatal development, the ability to recall episodic memories emerges later than other types of memory such as object recognition. However, the precise developmental trajectory of episodic memory, from weaning to adulthood has not yet been established in rats. Spontaneous object exploration tasks do not require training, and allow repeated testing of subjects, provided novel objects are used on each trial. Therefore, these tasks are ideally suited for the study of the ontogeny of episodic memory and its constituents (e.g., object, spatial, and contextual memory).MethodsIn the present study, we used four spontaneous short-term object exploration tasks over two days: object (OR), object-context (OCR), object-place (OPR), and object-place-context (OPCR) recognition to characterise the ontogeny of episodic-like memory and its components in three commonly used outbred rat strains (Lister Hooded, Long Evans Hooded, and Sprague Dawley).ResultsIn longitudinal studies starting at 3-4 weeks of age, we observed that short term memory for objects was already present at the earliest time point we tested, indicating that it is established before the end of the third week of life (consistent with several other reports). Object-context memory developed during the fifth week of life, while both object-in-place and the episodic-like object-place-context memory developed around the seventh postnatal week. To control for the effects of previous experience in the development of associative memory, we confirmed these developmental trajectories using a cross-sectional protocol.DiscussionOur work provides robust evidence for different developmental trajectories of recognition memory in rats depending on the content and/or complexity of the associations and emphasises the utility of spontaneous object exploration tasks to assess the ontogeny of memory systems with high temporal resolution.

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Early Developmental Low-Dose Methylmercury Exposure Alters Learning and Memory in Periadolescent but Not Young Adult Rats.

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Early Developmental Low-Dose Methylmercury Exposure Alters Learning and Memory in Periadolescent but Not Young Adult Rats.

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