Table 1.

Effects in microglia cells by essential metal.

Metal	Model	Time exposure	Concentration	Findings	Ref.
Manganese (Mn)	N9 murine microglial cell line	24 h	50-1000 μM MnCl2	↑ IL-6 and TNF-α production only at higher [MnCl2]	[101]
	HAPI rat microglia cell line. Primary microglia culture (SD rats)	0.25, 1, 3, 6, or 24 h	0.33, 1, 3.33, 10, or 3 μM MnCl2	↑ ERK and p38 activation in 10 μM of MnCl2 in 2 h	[102]
	N9 murine microglial cell line	15 min, 1, 3, 4 h	250 μM MnCl2	↑ p38 is critical for the Mn-induced potentiation of cytokine production.	[103]
	Primary microglia culture, C57BL6/J mouse	24 h	0, 10, 30, or 100 μM MnCl2	↑ Gene expression of NOS2, TNF-α, IL-1β, IL-6, and caspase 1. ↑ Transition to a mixed M1/M2 phenotype and debranched morphology	[104]
	BV2 cell line	6 h	100 μM MnCl2	↑ NLRP3-CASP1 inflammasome pathway	[132]
	Primary microglia culture, C57BL6/J mouse	24 h	0-100 μM MnCl2	↑ Expression of inflammatory genes NOS2, TNF-α, Cc15, IL-6, Ccr2, IL-1β	[105]
	BV2 cell line	24 h	30 μM MnCl2	↑ Autophagy dysfunction; role of LRRK2	[106]
	Primary microglia culture, C57BL6/J mouse ASC-CFP microglial cell line	3, 6, or 24 h	100 μM MnCl2	↑ NLRP3 and maturation of the inflammatory cytokine IL-1β	[107]
	Primary microglia cultures, C57BL6/J mouse	24 h	300 μM MnCl2	↑ Expression of Iba-1 and iNOS ↑ IL-12, IL-1β, and IL-6	[108]
	BV2 cell line	24 h	0, 100, and 500 μM MnCl2	↑ The expression level of APP, BACE1, amyloidogenic C99 fragment, and Aβ. ↑ IL-1β and TNF-α	[109]
Iron (Fe)	Primary microglia culture (SD rats)	24 h 30 min	5, 25, and 100 μM FeCl2	↑ Production O2•- and iROS, ↑morphological alteration. ↑ mRNA and protein levels of PKC-δ, P38, ERK1/2, JNK, and NF-κB (p65)	[118]
	BV2 cell line Primary microglia culture (SD rats)	24 h	100 μM FeSO4	↑ Levels of ROS	[116]
	Organotypic hippocampal culture (SD rats)	12 h	1 μM ferrocene C10H10Fe	↑ 15% in the number of Iba1-positive microglia	[114]
	Primary microglia culture, C57BL6/J mouse	6 or 24 h	20 μM FeCl3 and cytokine TNF-α (10 ng/mL) or TGF-β1 (5 ng/mL	TGF-β1 and TNF-α induce ↓ FPN mRNA levels at 24 h ↑ H-ferritin mRNA at 6 h in microglia	[117]
	Primary microglia culture, C57BL6/J mouse	24 h	100 μM ferric ammonium citrate, C6H8FeNO7	↑ Accumulation of iron	[115]
Copper (Cu)	BV2 cell line Primary microglia culture (SD rats)	12 h	20 μM CuCl2	↑ Levels of TNF-α, NO, and iNOS	[125]
	BV2 cell line Primary microglia culture (SD rats)	24 h	50 μM CuCl2 combined with Aβ 50 μM	↑ TNF-α and NO, ↑ iNOS	[126]
	BV2 cell line	24 h	0.01-5 μM CuSO4 0.01-5 μM of Aβ	↓ Phagocytic activation of BV2 cells ↑ IL-1β, TNF-α, and IL-6	[127]
Zinc (Zn)	Primary microglia culture, C57BL6/J mouse	90 min	30 μM ZnCl2	↑ Microglial activation. ↑ NF-κB and NO production ↑ F4/80 expression	[133]
	Primary microglia culture C57BL6/J mouse. BV2 cell line	2 h	30-60 μM ZnCl2	↑ iNOS mRNA	[134]
Cobalt (Co)	N9 cell line Primary microglia culture, Kunming mouse	24 h	1-500 μM CoCl2	↑ NO, cytokines (TNF-α and IL-6) and chemokines ↑ iNOS mRNA	[135]
	Primary microglia culture C57BL6/J mouse. BV2 cell line	3, 6, 9, or 18 h	100 μM CoCl2 stimulated with LPS. (0.25 μg/mL)	↑ Induces hypoxia factor 1 (HIF1) ↓ NLRP3 ↓Caspase 1 and IL-1β	[136]
	Primary microglia culture (SD rats) BV2 cell line	24 h	250 μM CoCl2	↑ HIF-1 and NF-κB in rat microglial culture	[137]

Sprague-Dawley (SD) rats; ferroportin (FPN).