Developmental neurotoxicity of the hippocampus following in utero exposure to methylmercury: impairment in cell signaling

• Published in: Archives of toxicology 2018-01, Vol.92 (1), p.513-527
• Main Authors: Heimfarth, Luana, Delgado, Jeferson, Mignori, Moara Rodrigues, Gelain, Daniel Pens, Moreira, José Cláudio Fonseca, Pessoa-Pureur, Regina
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Advanced glycosylation end products; AKT protein; Animals; Anxiety; Apoptosis; Astrocytes; Axonal transport; Bax protein; Bcl-2 protein; Bcl-x protein; Behavior, Animal - drug effects; Biomedical and Life Sciences; Biomedicine; Cascades; Caspase; Caspase-3; Cell death; Dimethylmercury; Environmental Health; Exploration; Exposure; Extracellular signal-regulated kinase; Female; Field tests; Glycogen Synthase Kinase 3 beta - metabolism; Hippocampus; Hippocampus - drug effects; Hippocampus - growth & development; Hippocampus - metabolism; Hippocampus - pathology; Intrauterine exposure; Kinases; Lipid Peroxidation - drug effects; Lysine; Male; MAP Kinase Signaling System - drug effects; Memory - drug effects; Mercury (metal); Methylmercury; Methylmercury Compounds - toxicity; Microtubules; Myelin; Neuronal-glial interactions; Neurotoxicity; Neurotoxicity Syndromes - etiology; Neurotoxicity Syndromes - pathology; Object recognition; Occupational Medicine/Industrial Medicine; Open-field behavior; Parturition; Pharmacology/Toxicology; Phosphatidylinositol 3-Kinases - metabolism; Pregnancy; Prenatal Exposure Delayed Effects; Proline; Protein kinase; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Wistar; Reproductive Toxicology; Rodents; Signal transduction; Signal Transduction - drug effects; Signaling
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-017-2042-6

In this study, we assessed some hippocampal signaling cascades and behavioral impairments in 30-day-old rat pups prenatally exposed to methylmercury (MeHg). Pregnant rats were exposed to 1.0 or 2.0 mg/kg MeHg by gavage in alternated days from gestational day 5 until parturition. We found increased anxiety-like and decreased exploration behavior evaluated by open field test and deficit of both short- and long-term memories by novel object recognition task, respectively, in MeHg-treated pups. Downregulated PI3K/Akt/mTOR pathway and activated/hypophosphorylated (Ser9) GSK3β in MeHg-treated pups could be upstream of hyperphosphorylated Tau (Ser396) destabilizing microtubules and contributing to neural dysfunction in the hippocampus of these rats. Hyperphosphorylated/activated p38MAPK and downregulated phosphoErk1/2 support a role for mitogen-activated protein kinase (MAPK) cascade on MeHg neurotoxicity. Decreased receptor of advanced glycation end products (RAGE) immunocontent supports the assumption that downregulated RAGE/Erk1/2 pathway could be involved in hypophosphorylated lysine/serine/proline (KSP) repeats on neurofilament subunits and disturbed axonal transport. Downregulated myelin basic protein (MBP), the major myelin protein, is compatible with dysmyelination and neurofilament hypophosphorylation. Increased glial fibrillary acidic protein (GFAP) levels suggest reactive astrocytes, and active apoptotic pathways BAD/BCL-2, BAX/BCL-XL, and caspase 3 suggest cell death. Taken together, our findings get light on important signaling mechanisms that could underlie the behavioral deficits in 30-day-old pups prenatally exposed to MeHg.