PMID- 28756503
OWN - NLM
STAT- MEDLINE
DCOM- 20180807
LR  - 20181113
IS  - 1476-3524 (Electronic)
IS  - 1029-8428 (Print)
IS  - 1029-8428 (Linking)
VI  - 32
IP  - 4
DP  - 2017 Nov
TI  - Gestational Age and Sex Influence the Susceptibility of Human Neural Progenitor 
      Cells to Low Levels of MeHg.
PG  - 683-693
LID - 10.1007/s12640-017-9786-x [doi]
AB  - The developing nervous system is highly susceptible to methylmercury (MeHg), a 
      widespread environmental neurotoxic contaminant. A wide range of morphological 
      and functional outcomes have been described; however, there are still open 
      questions regarding the mechanisms behind the developmental neurotoxic effects 
      induced by low-level exposure. In the present study, we have examined the effects 
      of nanomolar concentrations of MeHg on primary fetal human progenitor cells 
      (hNPCs) with special focus on the role played by developmental stage and sex on 
      the neurotoxic outcome. We found that neurospheres derived from earlier 
      gestational time points exhibit higher susceptibility to MeHg, as they undergo 
      apoptosis at a much lower dose (25 nM) as compared to neurospheres established 
      from older fetuses (100 nM). At subapoptotic concentrations (10 nM), MeHg 
      inhibited neuronal differentiation and maturation of hNPCs, as shown by a reduced 
      number of Tuj1-positive cells and a visible reduction in neurite extension and 
      cell migration, associated with a misregulation of Notch1 and BDNF signaling 
      pathways. Interestingly, cells derived from male fetuses showed more severe 
      alterations of neuronal morphology as compared to cells from females, indicating 
      that the MeHg-induced impairment of neurite extension and cell migration is 
      sex-dependent. Accordingly, the expression of the CDKL5 gene, a major factor 
      regulating neurite outgrowth, was significantly more downregulated in 
      male-derived cells. Altogether, gestational age and sex appear to be critical 
      factors influencing in vitro hNPC sensitivity to low levels of MeHg.
FAU - Edoff, Karin
AU  - Edoff K
AD  - Department of Neuroscience, Karolinska Institutet, Retzius vag 8, SE-171 77, 
      Stockholm, Sweden.
FAU - Raciti, Marilena
AU  - Raciti M
AUID- ORCID: 0000-0003-3161-3742
AD  - Department of Neuroscience, Karolinska Institutet, Retzius vag 8, SE-171 77, 
      Stockholm, Sweden. Marilena.Raciti@ki.se.
FAU - Moors, Michaela
AU  - Moors M
AD  - Department of Neuroscience, Karolinska Institutet, Retzius vag 8, SE-171 77, 
      Stockholm, Sweden.
FAU - Sundstrom, Erik
AU  - Sundstrom E
AD  - Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, 
      Geriatrik-lab plan 5, SE-141 52, Huddinge, Sweden.
FAU - Ceccatelli, Sandra
AU  - Ceccatelli S
AD  - Department of Neuroscience, Karolinska Institutet, Retzius vag 8, SE-171 77, 
      Stockholm, Sweden.
LA  - eng
GR  - 10815/Vetenskapsradet/
PT  - Journal Article
DEP - 20170729
PL  - United States
TA  - Neurotox Res
JT  - Neurotoxicity research
JID - 100929017
RN  - 0 (Methylmercury Compounds)
SB  - IM
MH  - Apoptosis/drug effects
MH  - Cell Cycle/drug effects
MH  - Cell Differentiation/drug effects
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Female
MH  - Gestational Age
MH  - Humans
MH  - Methylmercury Compounds/pharmacology
MH  - Neural Stem Cells/*cytology/drug effects
MH  - Neurogenesis/drug effects
MH  - Neurons/cytology/drug effects
PMC - PMC5602033
OTO - NOTNLM
OT  - Cell migration
OT  - Developmental neurotoxicity
OT  - Human neural progenitor cells
OT  - Methylmercury
OT  - Sex-related differences
COIS- The Regional Ethics Committee, Stockholm, Sweden (nos. 2008/158-33/3, 
      2011/1101-32) approved the procedure. CONFLICT OF INTEREST: The authors declare 
      that they have no conflict of interest.
EDAT- 2017/08/02 06:00
MHDA- 2018/08/08 06:00
PMCR- 2017/07/29
CRDT- 2017/07/31 06:00
PHST- 2016/12/14 00:00 [received]
PHST- 2017/07/12 00:00 [accepted]
PHST- 2017/07/09 00:00 [revised]
PHST- 2017/08/02 06:00 [pubmed]
PHST- 2018/08/08 06:00 [medline]
PHST- 2017/07/31 06:00 [entrez]
PHST- 2017/07/29 00:00 [pmc-release]
AID - 10.1007/s12640-017-9786-x [pii]
AID - 9786 [pii]
AID - 10.1007/s12640-017-9786-x [doi]
PST - ppublish
SO  - Neurotox Res. 2017 Nov;32(4):683-693. doi: 10.1007/s12640-017-9786-x. Epub 2017 
      Jul 29.