Perinatal exposure to lead induces morphological, ultrastructural and molecular alterations in the hippocampus

Baranowska-Bosiacka, Irena; Strużyńska, Lidia; Gutowska, Izabela; Machalińska, Anna; Kolasa, Agnieszka; Kłos, Patrycja; Czapski, Grzegorz A.; Kurzawski, Mateusz; Prokopowicz, Adam; Marchlewicz, Mariola; Safranow, Krzysztof; Machaliński, Bogusław; Wiszniewska, Barbara; Chlubek, Dariusz

doi:10.1016/j.tox.2012.10.027

Cited by 58 publications

(36 citation statements)

References 60 publications

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“…Endoplasmic reticulum (ER) stress, oxidative stress, and disrupted calcium homeostasis have also been implicated in lead-induced neurotoxicity and other target organ toxicities (Toscano and Guilarte, 2005a; White et al, 2007; Baranowska-Bosiacka et al, 2013; Liu et al, 2013a, b; Akande et al, 2014). For example, lead may bind to sulfhydryl groups, leading to a reduction in cellular antioxidant capacity through the depletion of the cellular thiol status and inhibition of antioxidant enzymes, inducing oxidative stress (Ercal et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Lead decreases cell survival, proliferation, and neuronal differentiation of primary cultured adult neural precursor cells through activation of the JNK and p38 MAP kinases

Engstrom

Wang

Xia

2015

Toxicology in Vitro

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Adult hippocampal neurogenesis is the process whereby adult neural precursor cells (aNPCs) in the subgranular zone (SGZ) of the dentate gyrus (DG) generate adult-born, functional neurons in the hippocampus. This process is modulated by various extracellular and intracellular stimuli, and the adult-born neurons have been implicated in hippocampus-dependent learning and memory. However, studies on how neurotoxic agents affect this process and the underlying mechanisms are limited. The goal of this study was to determine whether lead, a heavy metal, directly impairs critical processes in adult neurogenesis and to characterize the underlying signaling pathways using primary cultured SGZ-aNPCs isolated from adult mice. We report here that lead significantly increases apoptosis and inhibits proliferation in SGZ-aNPCs. In addition, lead significantly impairs spontaneous neuronal differentiation and maturation. Furthermore, we found that activation of the c-Jun NH2-terminal kinase (JNK) and p38 mitogen activated protein (MAP) kinase signaling pathways are important for lead cytotoxicity. Our data suggest that lead can directly act on adult neural stem cells and impair critical processes in adult hippocampal neurogenesis, which may contribute to its neurotoxicity and adverse effects on cognition in adults.

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Section: Discussionmentioning

confidence: 99%

Lead decreases cell survival, proliferation, and neuronal differentiation of primary cultured adult neural precursor cells through activation of the JNK and p38 MAP kinases

Engstrom

Wang

Xia

2015

Toxicology in Vitro

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“…Prenatal and postnatal Pb exposures disrupt the developing hippocampus in animals models (Baranowska-Bosiacka et al, 2013; Schneider et al, 2001), and the hippocampus plays an important role in the neural circuits related to recognition memory (McGaugh et al, 1996; Nelson, 1995; Siddappa et al, 2004). Therefore, hippocampal dysfunction might be the neural underpinning for the adverse effect of prenatal Pb exposure on recognition memory in 2-month-old infants.…”

Section: Discussionmentioning

confidence: 99%

“…Recognition memory, the capability to retrieve previously encountered events or material, steadily improves during the first year of life (Nelson & Collins, 1992; Rose, 1983). The hippocampus and related structures are important neural substrates for recognition memory (McGaugh, Cahill, & Roozendaal, 1996; Nelson, 1995; Siddappa et al, 2004), and animal models show that both prenatal and postnatal Pb exposures have detrimental effects on the developing hippocampus (Baranowska-Bosiacka et al, 2013; Schneider, Lee, Anderson, Zuck, & Lidsky, 2001). Thus, infants’ recognition memory might be vulnerable to prenatal Pb exposure.…”

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confidence: 99%

Low-Level Prenatal Lead Exposure Alters Auditory Recognition Memory in 2-Month-Old Infants: An Event-Related Potentials (ERPs) Study

Geng¹,

Mai²,

Zhan³

et al. 2014

Developmental Neuropsychology

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This study used event-related potentials to assess effects of low-level prenatal lead exposure on auditory recognition memory in 2-month-old infants. Infants were divided into four groups according to cord-blood lead concentration: 1) < 2.00 μg/dL, 2) 2.00-2.99 μg/dL, 3) 3.0-3.7 μg/dL, and 4) ≥ 3.7 μg/dL. The first group showed the normally expected differences in P2, P750, and LSW amplitudes elicited by mothers’ and strangers’ voices. These differences were not observed for one or more ERP components in the other groups. Thus, there was electrophysiological evidence of poorer auditory recognition memory at 2 months with cord-blood lead ≥ 2.00 μg/dL.

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“…Additionally, mice exposed to lead in utero have also neurochemistry alterations in the hippocampus, including increment of myoinositol/creatine (Ins/Cr) and glutamine (Gln) (Lindquist, unpublished ). Recently, gestational lead exposure in Wistar rats was shown to reduce the number of pyramidal cells in the hippocampus (Baranowska-Bosiacka et al 2013). In addition, differentiation of embryonic stem cells into glutamatergic neurons in the presence of lead caused alterations in the expression of glutamate receptor subunits Grin1, Grin2D, Grik5, Gria4 , and Grm6 that were also observed in hippocampus and cortex of mice gestationally exposed to this metal (Sanchez-Martin et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Sex- and tissue-specific methylome changes in brains of mice perinatally exposed to lead

et al. 2015

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Changes in DNA methylation and subsequent changes in gene expression regulation are the hallmarks of age- and tissue-dependent epigenetic drift and plasticity resulting from the combinatorial integration of genetic determinants and environmental cues. To determine whether perinatal lead exposure caused persistent DNA methylation changes in target tissues, we exposed mouse dams to 0, 3 or 30 ppm of lead acetate in drinking water for a period extending from 2 months prior to mating, through gestation, until weaning of pups at postnatal day-21, and analyzed whole-genome DNA methylation in brain cortex and hippocampus of 2-month old exposed and unexposed progeny. Lead exposure resulted in hypermethylation of three differentially methylated regions in the hippocampus of females, but not males. These regions mapped to Rn4.5s, Sfi1, and Rn45s loci in mouse chromosomes 2, 11 and 17, respectively. At a conservative fdr<0.001, 1,623 additional CpG sites were differentially methylated in female hippocampus, corresponding to 117 unique genes. Sixty of these genes were tested for mRNA expression and showed a trend towards negative correlation between mRNA expression and methylation in exposed females but not males. No statistically significant methylome changes were detected in male hippocampus or in cortex of either sex. We conclude that exposure to lead during embryonic life, a time when the organism is most sensitive to environmental cues, appears to have a sex- and tissue-specific effect on DNA methylation that may produce pathological or physiological deviations from the epigenetic plasticity operative in unexposed mice.

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Perinatal exposure to lead induces morphological, ultrastructural and molecular alterations in the hippocampus

Cited by 58 publications

References 60 publications

Lead decreases cell survival, proliferation, and neuronal differentiation of primary cultured adult neural precursor cells through activation of the JNK and p38 MAP kinases

Lead decreases cell survival, proliferation, and neuronal differentiation of primary cultured adult neural precursor cells through activation of the JNK and p38 MAP kinases

Low-Level Prenatal Lead Exposure Alters Auditory Recognition Memory in 2-Month-Old Infants: An Event-Related Potentials (ERPs) Study

Sex- and tissue-specific methylome changes in brains of mice perinatally exposed to lead

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