Table 3.

Evidence supporting adverse outcome pathway (AOP) network for histone methylation (Figure 1B).

Key event	Event description	Key event relationship	Reference
Exposure
IE	Arsenic exposure	Sources of human exposure to inorganic arsenic include drinking water, diet, air, and soils (which can contain naturally occurring arsenic or contamination from anthropogenic sources).	(ATSDR 2007)
Molecular
KE7	Decreased histone acetylase or increased histone deacetylase activity	Arsenic exposure increased the histone acetyltransferase GCN5 in the DG, whereas GCN5 was decreased in the FC.	(Chervona et al. 2012)
KE8	Increased histone methyltransferase or decreased histone demethylase activity	Developmental arsenic exposure ($50\text{ppb}$ decreased histone demethylase KDM5B and increased expression of the histone methyltransferase MLL in the DG and FC of male mice only.	(Tyler et al. 2015a, 2015b)
KE9	Decreased H3K9ac	In vivo arsenic exposure was negatively correlated with global H3K9ac levels in peripheral blood mononuclear cells in a sex-specific manner. Histone acetyltransferase GCN5 was increased in the DG, whereas H3K9ac and GCN5 were decreased in the FC.	(Chervona et al. 2012)
KE10	Increased H3K4me3	Developmental arsenic exposure ($50\text{ppb}$) increased global H3K4me3 levels.	(Tyler et al. 2015a, 2015b)
Individual
AO3	Psychiatric and neurological disorders	Arsenic exposure was positively correlated with developing psychiatric disorders and cognitive dysfunction.	(Brinkel et al. 2009; Zierold et al. 2004)

Note: AO, adverse outcome; DG, dentate gyrus; FC, frontal cortex; IE, initiating event; KE, key event.