title: Delay and impairment in brain development and function in rat offspring after maternal exposure to methylmercury.
abstract: Maternal exposure to the neurotoxin methylmercury (MeHg) has been shown to have adverse effects on neural development of the offspring in man. Little is known about the underlying mechanisms by which MeHg affects the developing brain. To explore the neurodevelopmental defects and the underlying mechanism associated with MeHg exposure, the cerebellum and cerebrum of Wistar rat pups were analyzed by [(18)F]FDG PET functional imaging, field potential analysis, and microarray gene expression profiling. Female rat pups were exposed to MeHg via maternal diet during intrauterinal and lactational period (from gestational day 6 to postnatal day (PND)10), and their brain tissues were sampled for the analysis at weaning (PND18-21) and adulthood (PND61-70). The [(18)F]FDG PET imaging and field potential analysis suggested a delay in brain activity and impaired neural function by MeHg. Genome-wide transcriptome analysis substantiated these findings by showing (1) a delay in the onset of gene expression related to neural development, and (2) alterations in pathways related to both structural and functional aspects of nervous system development. The latter included changes in gene expression of developmental regulators, developmental phase-associated genes, small GTPase signaling molecules, and representatives of all processes required for synaptic transmission. These findings were observed at dose levels at which only marginal changes in conventional developmental toxicity endpoints were detected. Therefore, the approaches applied in this study are promising in terms of yielding increased sensitivity compared with classical developmental toxicity tests.
authors: TNO, 3700 AJ Zeist, The Netherlands.
authors: Marijana
authors: M
authors: Radonjic
authors: Natalie L M
authors: NL
authors: Cappaert
authors: Erik F J
authors: EF
authors: de Vries
authors: Celine E F
authors: CE
authors: de Esch
authors: Frieke C
authors: FC
authors: Kuper
authors: Aren
authors: A
authors: van Waarde
authors: Rudi A J O
authors: RA
authors: Dierckx
authors: Wytse J
authors: WJ
authors: Wadman
authors: André P M
authors: AP
authors: Wolterbeek
authors: Rob H
authors: RH
authors: Stierum
authors: Didima M G
authors: DM
authors: de Groot
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D019788:Fluorodeoxyglucose F18; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055106:Genome-Wide Association Study; D005865:Gestational Age; D007774:Lactation; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D008767:Methylmercury Compounds / Q000633:toxicity*; D055495:Neurogenesis / Q000187:drug effects*; D049268:Positron-Emission Tomography; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D059467:Transcriptome / Q000187:drug effects
chemical_list: D004785:Environmental Pollutants; D008767:Methylmercury Compounds; D019788:Fluorodeoxyglucose F18; C004925:methylmercuric chloride