The brain is an important

The Hydrocortisone is an important target organ for exogenous stimulation, including DBP (Wójtowicz et al., 2017), while the hippocampus is a key functional region for learning and memory (Whitlock et al., 2006). There is emerging evidence that phthalate including DBP may have deleterious effects on the developing brain in 0–12-year-old children with behavioral problems (Ejaredar et al., 2015). The supporting laboratory studies and proposed mechanisms underlying the adverse impacts of DBP in relation to hippocampal toxicity have also been reported (Holahan and Smith, 2015). Moreover, DBP-induced apoptosis in the hippocampal neurons of DBP-exposed immature rats are also demonstrated (Li et al., 2013; Wójtowicz et al., 2017). Although the observed associations are based on limited studies with a broad range of endpoints, the implications of such outcomes are of concern from a public health standpoint and merit further investigation given the non-negligible influence of the DBP exposure to those LDs (Miodovnik et al., 2014). Recent studies have shown that the extracellular regulated protein kinase 1 and 2 (ERK1 and ERK2), commonly referred to collectively as ERK 1/2, are members of the mitogen-activated protein kinase (MAPK) family. This family of kinases transport signals from the surface of the cell to the nucleus, thereby mediating the activation of nuclear transcription factors that participate in cell apoptosis and other biological functions (Cargnello and Roux, 2011; Ciccarelli and Giustetto, 2014). ERK 1/2, and their phosphorylations (p-ERK 1/2) play a notable role in neurobehavioral responses and cognitive processes that include learning and memory (Johnson and Lapadat, 2002). In addition, di-(2-ethylhexyl) phthalate, a homologue of DBP, can induce excessive reactive oxygen species (ROS) and cause calcium aggravation in hepatocytes, which were isolated from the liver of male albino rats of the Wistar strain weighing approximately 120–130 g (4 weeks of age), exposed to DEHP for 24 h at doses of 5, 10, 25, 50, 100, and 200 μM (Ghosh et al., 2010). But even more importantly, intracellular ROS accumulation and a Ca2+ imbalance can activate the ERK 1/2 pathways in hippocampal neurons (Mccubrey et al., 2006; Kemmerling et al., 2007). On the basis of there being a possible relationship between DBP and the ERK 1/2 pathway, we conducted this research to determine whether DBP induces hippocampal neuron apoptosis and whether it increases the observed behavioral disorders via the ERK 1/2 pathway. We examined the ROS, GSH and MDA content to evaluate oxidative stress. The levels of CaM, CaMK II and PKC were examined to assess the Ca2+ signaling pathway. We determined ERK 1/2 and ERK 1/2 pathway-related proteins (sensitive biomarkers) including BDNF and p-CREB levels after DBP treatment to study the role of ERK 1/2 in DBP-mediated effects. The levels of cyto C, caspase-3 and TNF-α were also analysised to evaluate apoptosis in hippocampal neurons. We also looked for changes in mouse behavior, and observed histopathological changes and immunohistochemistry in the hippocampus. In addtion, we used the antioxidant VE and the DHP Ca2+ antagonist, NMDP, to demonstrate that the ERK 1/2 pathway mediates oxidative stress and the Ca2+ signaling pathway induced by DBP. Although this study is an animal experiment, it still provides a better understanding of the possible mechanism by which neurotoxic environmental pollutants induce LDs in children.