Evaluation of changes in methylmercury accumulation in the developing rat brain and its effects: a study with consecutive and moderate dose exposure throughout gestation and lactation periods

Sakamoto, Mineshi; Kakita, Akiyoshi; Wakabayashi, Keiji; Takahashi, Hitoshi; Nakano, Atsuhiro; Akagi, Hirokatsu

doi:10.1016/s0006-8993(02)02964-5

Cited by 132 publications

(58 citation statements)

References 34 publications

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“…Our observations of cell cycle effects of MeHg in vivo occur at Hg levels (probablỹ 200-300ng/g, given use of 3mg/kg MeHg for proliferation studies and a measured level of 700-900ng/g after 10mg/kg) achieved with chronic dosing and also associated with long-term behavioral effects (Rossi et al, 1997;Newland and Reile, 1999;Sakamoto et al, 2002). Whether MeHg is delivered as a single injection (our study) or a chronic low dose oral exposure, similar mercury levels are associated with altered cell production and future behavioral effects (Rossi et al, 1997;Newland and Reile, 1999;Castoldi et al, 2001;Goulet et al, 2003).…”

Section: Long-term Effects Of Mehg Suggests Alteration In Brain Regiomentioning

confidence: 74%

“…In neonatal rat brain, mercury accumulation (Sakamoto et al, 2002) and pathology (Wakabayashi et al, 1995) are regionally dependent on postnatal age. At P1, mercury distributes equally (Sakamoto et al, 2002) and produces histological disruption in hippocampus but not cerebellum (Wakabayashi et al, 1995). Our study defined similar differential effects on proliferation in hippocampus and cerebellum at P7.…”

Section: Mehg Has Rapid Differential Effects On Proliferation In Devmentioning

confidence: 99%

“…MeHg effects at earlier phases of the cell cycle have been identified but are less welldefined (Roy et al, 1991;Faustman et al, 2002). In addition, many MeHg studies on cellular toxicity (Castoldi et al, 2001), neurogenesis , and long-term effects (Goulet et al, 2003;Rossi et al, 1997;Sakamoto et al, 2002) have used chronic dosing or timepoints ≥ 24h. Few studies have investigated early, single-dose effects on neurogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E

Burke

Cheng

et al. 2006

NeuroToxicology

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The developing brain is highly sensitive to methylmercury (MeHg). Still, the initial changes in cell proliferation that may contribute to long-term MeHg effects are largely undefined. Our previous studies with growth factors indicate that acute alterations of G1/S phase transition can permanently affect cell numbers and organ size. Therefore, we determined whether an environmental toxicant could also impact brain development with rapid (6-7h) effects on DNA synthesis and cell cycle machinery in neuronal precursors. In vivo studies in newborn rat hippocampus and cerebellum, two regions of postnatal neurogenesis, were followed by in vitro analysis of two precursor models, cortical and cerebellar cells, focusing on the proteins that regulate G1/S transition. In postnatal day 7 (P7) pups, a single subcutaneous injection of MeHg (3μg/g) acutely (7h) decreased DNA synthesis in the hippocampus by 40% and produced long-term (2 weeks) reductions in total cell number, estimated by DNA quantification. Surprisingly, cerebellar granule cells were resistant to MeHg effects in vivo at comparable tissue concentrations, suggesting region-specific differences in precursor populations. In vitro, MeHg altered proliferation and cell viability, with DNA synthesis selectively inhibited at an early timepoint (6h) corresponding to our in vivo observations. Considering that G1/ S regulators are targets of exogenous signals, we used a well-defined cortical cell model to examine MeHg effects on relevant cyclin dependent kinases (CDK) and CDK inhibitors. At 6h, MeHg decreased by 75% levels of cyclin E, a cell cycle regulator with roles in proliferation and apoptosis, without altering p57, p27, or CDK2 nor levels of activated caspase 3. In aggregate, our observations identify the G1/S transition as an early target of MeHg toxicity and raise the possibility that cyclin E degradation contributes to both decreased proliferation and eventual cell death.

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Section: Long-term Effects Of Mehg Suggests Alteration In Brain Regiomentioning

confidence: 74%

Section: Mehg Has Rapid Differential Effects On Proliferation In Devmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E

Burke

Cheng

et al. 2006

NeuroToxicology

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“…Numerosos estudios en animales han mostrado que estas células son especialmente vulnerables a muy diversos insultos, entre los que destaca la exposición a metales pesados (Hg, plomo, arsénico, cadmio y bismuto) ( [117][118][119][120][121][122][123] ), dañando sus receptores recaptadores de glutamato. La excesiva estimulación neuronal asociada a niveles elevados de glutamato intracerebrales aumenta la producción de especies reactivas de oxígeno, lo que a su vez induce estrés oxidativo, citotoxicidad y daño neuronal ( 124,125 ), razón por la que se ha postulado que, la exposición a metales pesados en fases muy tempranas de la vida, puede iniciar toda esta cadena de eventos que conducen, finalmente, a la muerte neuronal ( 126 ).…”

Section: Resultsunclassified

Efectos neurotóxicos del timerosal, a dosis de vacuna, sobre el encéfalo y el desarrollo en hámsteres de 7 días de nacidos

et al. 2013

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“…Thus, the condition of low dose (or low concentration) was probably met in the present study. Regarding the second condition, asynchronicity, as the accessible information indicates, the MeHg transfer from mother to the child occurs mainly through blood [47], whereas PCB is transferred mainly through milk [48,49]. It means that, in Experiment 3, during pregnancy the progeny was exposed mainly to MeHg and mainly to PCB 153 during lactation.…”

Section: Effects Of Exposure To Pcb 153mentioning

confidence: 98%

Neurobehavioural functions in adult progeny of rat mothers exposed to methylmercury or 2,2', 4,4', 5,5'-hexachlorobiphenyl (PCB 153) alone or their combination during gestation and lactation

Gralewicz¹,

Wiaderna²,

Lutz³

et al. 2009

International Journal of Occupational Medicine and Environmental Health

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Objectives: Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are ubiquitous environmental pollutants. Both are neurotoxic, especially for the developing brain. The main source of human exposure to MeHg and PCBs is seafood. The aim of the present work was to find out whether and how separate or combined perinatal exposure to these neurotoxicants affects neurobehavioural functions in maturity. Materials and Methods: The study was performed on adult Wistar rats, the progeny of rat mothers exposed to MeHg (0.5 mg/kg/day or 2.0 mg/kg/day), PCB 153 (1.0 mg/kg/day or 5.0 mg/kg/day), or to MeHg 0.5 mg/kg/day + PCB 153 5.0 mg/kg/day, from day 7 of pregnancy to day 21 post partum. The following functions were assessed: spontaneous locomotor activity (open field test), spatial short-term memory (radial maze test), long-term memory (passive avoidance test), sensitivity to pain and vulnerability to stress (hot plate test), efficiency of the sensorimotor gating (startle response test), and sensorimotor coordination (the rotarod test). Results:The results obtained in the MeHg part of the study showed a reduced locomotor activity in the female progeny of both exposed groups, an impaired passive avoidance in the male progeny of the high and low exposure group and a faster recovery from the effects of the stressful experience (hot plate test) in the male progeny of the high dose group. Results obtained in the PCB part showed an increased locomotor activity in the female progeny of both exposure groups and impairment in rotarod performance in males of the high dose group. Neurobehavioural alterations were not found in either the females or males exposed jointly to MeHg and PCB 153. Conclusions: The results suggest that in condition of the combined exposure, MeHg may protect against the effects of PCB 153 and vice versa.

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Evaluation of changes in methylmercury accumulation in the developing rat brain and its effects: a study with consecutive and moderate dose exposure throughout gestation and lactation periods

Cited by 132 publications

References 34 publications

Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E

Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E

Efectos neurotóxicos del timerosal, a dosis de vacuna, sobre el encéfalo y el desarrollo en hámsteres de 7 días de nacidos

Neurobehavioural functions in adult progeny of rat mothers exposed to methylmercury or 2,2', 4,4', 5,5'-hexachlorobiphenyl (PCB 153) alone or their combination during gestation and lactation

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