Table 1.

Studies investigating the effects of heavy metals on adult neurogenesis.

Metal	Model	Exposure	Effect	Reference
Cadmium	C57BL/6 mice; Nestin-CreER™:caMEK5-eGFPloxP/loxP (caMEK5) mice	0.6 mg/L Cd as CdCl2 through drinking water; start at 12-week-old for 16–18.5 weeks. (C57BL/6); start at 15–17-week-old for 38 weeks (caMEK5)	No effect on cell proliferation (2h BrdU+); impaired neuronal differentiation (2.5-week BrdU+/NeuN+, 2.5-week BrdU+/DCX+) and dendritic complexity of immature neurons in SGZ. Inducible and conditional expression of caMEK5 in aNPCs (stimulating adult neurogenesis) rescued animals from Cd-induced impairments of adult hippocampal neurogenesis and related spatial memory (novel object location test, contextual fear memory test)	[8]
Cadmium	C57BL/6 mice; Nestin-CreER™:caMEK5-eGFPloxP/loxP (caMEK5) mice	0.6 mg/L Cd as CdCl2 through drinking water; start at 12-week-old for 16–18.5 weeks. (C57BL/6); start at 15–17-week-old for 38 weeks (caMEK5)	No effect on cell proliferation (2h BrdU+) in SVZ; impaired neuronal differentiation (2.5-week BrdU+/NeuN+, 2.5-week BrdU+/DCX+) in OB. Inducible and conditional expression of caMEK5 in aNPCs (stimulating adult neurogenesis) rescued animals from Cd-induced impairments of SVZ neurogenesis and related olfactory memory (short term olfactory memory test, odor-cued associative learning and memory test)	[9]
Cadmium	C57BL/6 mice	3 mg/L Cd as CdCl2 through drinking water; start at 8-week-old for 20 weeks	Impaired hippocampus-dependent spatial working memory in novel object location test and T-maze test; impaired contextual fear memory. Impaired olfactory memory in short-term olfactory memory test and odor-cued associative learning and memory test.	[17]
Cadmium	SGZ aNPCs; C57BL/6 mice	0–0.45 μΜ CdCl2 (in vitro); 3 mg/L Cd as CdCl2 through drinking water; start at 8-week-old for 13 weeks (in vivo).	Induced apoptosis, inhibited cell proliferation (BrdU+) and spontaneous neuronal differentiation (β-ΙΙΙ tubulin+); induced activation of JNK and p38 MAP kinase pathway in vitro. Decreased cell survival (5-week BrdU+) without impairment of cell proliferation (Ki67+); Impaired cell differentiation (5-week BrdU+/DCX+) and maturation (5-week BrdU+/NeuN+) in DG; decreased dendritic complexity in immature DG neurons in vivo	[18]
Cadmium	SVZ aNPCs	0–0.45 μΜ CdCl2	Induced apoptosis, impaired cell proliferation (BrdU+); induced activation of JNK and p38 MAP kinase pathway	[19]
Cadmium	ApoE3/ApoE4-KI mice	0.6 mg/L CdCl2 through drinking water; start at 8-week-old for 14 weeks.	Impaired spatial working memory in novel object location test; deficits manifested earlier in ApoE4 mice than ApoE3 mice within the same sex and earlier in males within the same genotype. Impaired neuronal differentiation of adult-born neurons in hippocampus of male ApoE4 mice	[20]
Cadmium	Swiss Albino mice	2.5 mg/kg/day oral dose Cd; start from 4-week-old for 60 days	Impaired spatial learning and memory in Morris water maze test; impaired novel object recognition memory. Induced oxidative stress, reduced proteins associated with neurogenesis (hippocampus BDNF, synapsin II, DCX, CREB).	[21]
Cadmium	Murine neural stem cells	0.75, 1.5 μΜ CdCl2	Decreased differentiation into immature neurons, increased differentiation into astrocytes.	[22]
Lead	ApoE3/ApoE4-KI mice	0.2% Lead acetate through drinking water; start from 8-week-old for 12 weeks	Impaired proliferation (2h BrdU+), neuronal differentiation (3-week BrdU+/DCX+), and maturation (3-week BrdU+/NeuN+) of aNPCs in DG; decreased dendritic complexity of immature neurons in SGZ of female ApoE4 mice. Impaired hippocampus-dependent spatial memory in novel object location test in all mice but manifested first in female ApoE4-KI mice; reduced contextual fear memory in all animals; decreased spontaneous alternation in T-maze in female ApoE4 mice.	[10]
Lead	SGZ aNPCs	0–2 μΜ Lead as Lead acetate	Induced apoptosis, inhibited proliferation (BrdU+), and impaired spontaneous neural differentiation (β-ΙΙΙ tubulin+); induced activation of JNK and p38 MAP kinase pathway.	[25]
Lead	Long Evans rats	0.2% Lead acetate through drinking water; start rom gestation day 16	Decreased survival of adult-born cells (BrdU+ ;28 days after last BrdU dosing, postnatal day 114); did not affect cell proliferation (BrdU+;24 h after last BrdU dosing, postnatal day 86) in SGZ.	[26]
Lead	Long Evans rats	1500 ppm Lead acetate in diet; from 10 days before breeding to postnatal day 50 for proliferation study; to postnatal day 78 for survival study	Impaired cell proliferation (24h BrdU+) and survival (4-week BrdU+) of aNPCs; reduced dendritic length of newly born granule cells, did not affect cellular fate of newly born cells (Brdu+/DCX+ or BrdU+/GFAP+) in DG.	[27]
Lead	Wistar rats	0.2% Lead acetate through drinking water; from postnatal day 1 to postnatal day 30	Reduced cell proliferation (24h BrdU+) and neuronal differentiation (3-week BrdU+/Calbindin+) in SGZ; did not affect survival of adult-born cells in SGZ. Impaired contextual fear memory.	[28]
Mercury	Sprague-Dawley rats	0.6 μg/g or 5 μg/g Methylmercury as Methylmercury chloride; subcutaneous injection, single dose	Induced caspase-dependent apoptosis; reduced proliferating cells (BrdU+) in DG. Impaired hippocampus-dependent spatial memory in Morris water maze test.	[11]
Mercury	Sprague-Dawley rats	0.4 mg/kg Methylmercury as Methylmercury chloride; intraperitoneal injection; once a day from postnatal day 5-day 33	Decreased number of immature neurons (DCX+) in the SGZ. Impaired hippocampus-dependent spatial memory in Morris water maze test.	[12]
Mercury	Murine-derived neural stem cell line C17.2	0–2 μΜ Methylmercury	Induced apoptosis through activation of caspase-3 and Bax.	[31]
Mercury	Human neural progenitor cells (ReNcell CX cells)	0, 10 and 50 nM Methylmercury	Deceased mitochondrial function, induced apoptosis, and induced ROS generation.	[32]
Mercury	Sprague-Dawley rats	5 μg/kg Dimethylmercury; intraperitoneal injection, once a day for 36 days	Reduced number of proliferating cells and immature neurons in SGZ. Impaired hippocampus-dependent spatial memory in Morris water maze test and novel object recognition test.	[33]
Arsenic	Kunming mice	4 mg/L As2O3 through drinking water; group1: 4 months; group2: 4 months + 2 months recover	Reduced number of adult-born (BrdU+) cells and adult-born mature neurons (BrdU+/NeuN+); did not induce apoptosis in hippocampus; deficits were reversible after arsenic removed. Wnt3 mRNA levels decreased in the treated group.	[37]
Arsenic	C57BL/6 mice	50 ppb Arsenic through drinking water; from breeding to Postnatal day 23–25.	Reduced total number of 4-week-old adult-born immature (BrdU+/DCX+) and mature (BrdU+/NeuN+) neurons; did not affect number of proliferating cells (12h-labeling BrdU+/Ki67+) in SGZ. Alteration in expression levels of neurogenesis-related genes, such as Dcx, Fgf2, and Nf1.	[39]
Arsenic	C57BL/6 mice	50 ppb Arsenic through drinking water; from 10 days before mating to Postnatal day 23–25.	Affected histone modification, including H3K4me3 and H3k9ac, along with protein expression of their chromatin modifiers in DG.	[40]
Arsenic	Swiss Albino mice	2 mg/kg As2O3; oral gavage for 45 days	Impaired spatial working memory in Morris water maze test.	[42]
Arsenic	Swiss Albino mice	100 mg/L Sodium arsenite; through drinking water for 60 days	Impaired spatial working memory in Morris water maze test.	[43]
Manganese	SVZ aNPCs	0–800 μΜ Manganese as MnCl2	Reduced total neurites length of differentiated SVZ aNPCs; cytoskeletal reorganization; impaired neuronal differentiation (DCX+).	[47]
Manganese	Sprague-Dawley rats	6 mg/kg as MnCl2; intraperitoneal injection, once per day, 5 days per week for 4 weeks	Increased proliferation (4h BrdU+) of aNPCs in SVZ; decreased survival rate of adult-born neurons (BrdU+/NeuN+) in OB.	[48]
Manganese	Sprague-Dawley rats	6 mg/kg Manganese as MnCl2; intraperitoneal injection, once per day, 5 days per week for 4 weeks	Inhibited proliferation of aNPCs; impaired survival rate of adult-born cells (2-week and 4-week BrdU+); reduced number of adult-born immature (BrdU+/DCX+) and mature neurons (BrdU+/NeuN+) in SGZ.	[49]
Manganese	Sprague-Dawley rats	6.55 mg/kg Manganese as MnCl2 for 4, 8, and 12 weeks	Impaired hippocampus-dependent spatial memory in Morris water maze test.	[50]
Manganese	Mice	100 mg/kg Manganese as MnCl2; intraperitoneal injection; once per day for 3 days with 3 days interval	Impaired hippocampus-dependent contextual fear memory.	[51]