Table 1:

Summary of p38- and ERK-MAPK involvement in CNS response to environmental toxicants

Environmental Toxins	Mechanism	Species/Model	Dose	Exposure time/duration	References
Manganese	Mn-induced neuronal apoptosis via the activation of PKA or Ca2+/p38-MAPK/CREB signaling	PC12 cells and mouse brain tissue	Mice - 20 mg/kg	Mice - Daily intraperitoneal injections for 60 days	(Zhu et al., 2019)
	Mn-induced oxidative stress via increased LRRK2/p38- and ERK-MAPK signaling	Human microglial cells	MnCl2 - 250 μM	24 hours	(Kim et al., 2019)
	Mn-induced inflammation via p38-and ERK-MAPK/COX-2 signaling pathways	Rat thalamus and hippocampus	MnCl2·4H2O - 15 mg/kg	12 weeks	(Li et al., 2018)
Cadmium	Cd-induced cell death via that Cd-Ca2+-p38/ERK-MAPK signaling pathway	Cerebral cortical astrocytes	10 μM CdCl2 (chronic exposure)	12 hours (chronic exposure)	(Jiang et al., 2015).
			100 or 300 μM CdCl2 (acute exposure)	0.5–2 hours (acute exposure)
	Cd-induced apoptotic cell death via ROS-mediated increase in ERK1/2 and p38 signalling	PC12 and primary neurons from mouse cerebral cortex	10 μM and 20 μM CdCl2	24 hours	(Xu et al., 2016)
	Cd-induced neuroinflammation via increased production of IL-6 and IL-8 ERK1/2 and p38 pathways	U-87 MG cells	10 μM CdCl2	3 hours	(Kasemsuk et al., 2020)
	Neuroinflammation via γ-secretase/p38-MAPK/CREB-mediated increased COX-2 expression	C6 astrocytes cells	10 and 25 μM CdCl2	6 hours	(Lim et al., 2019).
Mercury	Neuronal loss via p38-MAPK/CREB/c-fos/BDNF upregulation.	Mice	30 ppm MeHg	8 weeks	(Fujimura and Usuki, 2017)
	Mercuric chloride-induced DNA fragmentation and cell death via elevated p38- and ERK-MAPK/Bax/caspase-3 signaling	Rat	5 mg/kg HgCl2	14 days	(Fadda et al., 2020)
	Mercuric chloride-induced inflammation evident by an elevation in serum level of TNF-α and IL-6 via p38- and ERK-MAPK activation	Rat	5 mg/kg HgCl2	14 days	(Fadda et al., 2020)
Chlorpyrifos	Apoptotic cell death via increased caspase-3 mediated by p38- and ERK-MAPK signaling pathways	PC12 cells	100 and 200 μM	24 hours	(Lee et al., 2012)
	Cytotoxicity and neuronal death due to increased p-p38 and p-ERK expression and subsequently increased caspase-3 levels.	SH-SY5Y cells	100 μM	24 hours	(Ki et al., 2013)
	Elevated ROS production via increased p38- and ERK-MAPK/ NF-κB signaling	SH-SY5Y cells	50 – 200 μM	24 hours	(Lee et al., 2014)
Soman	Increased p38-MAPK phosphorylation	Cerebellar Purkinje cells	60 μg/kg	One dose	(Pejchal et al., 2009).
Perfluorooctane sulfonic acid	Increased TNF-α and IL-6 expression partly by increased ERK1/2-MAPK/ NF-κB	BV2 microglial cells	0.1–10 μM	6 or 12 hours	(Zhu et al., 2015)
Tetrachloro-p-benzoquinone	p38, ERK, and JNK mediated increase of TNF-α, IL-1β and IL-6	Rat pheochromocytoma PC12 cells	25 μM	6 hours	(Fu et al., 2017).
Benzophenone-3	p38-MAPK-mediated apoptotic cell death.	mouse neuronal cell (hippocampal and neocortical) culture	25–100 μM	6 or 24 hours	(Wnuk et al., 2018)
Triphenyl phosphate	p38-, ERK-, and JNK-MAPK/FoxO-mediated apoptotic cell death in the cortex, thalamus, and hippocampus.	C57/BL6 mice	50 or 100 mg/kg	30 days	(Liu et al., 2020)