Exposure to di-(2-ethylhexyl) phthalate transgenerationally alters anxiety-like behavior and amygdala gene expression in adult male and female mice

Abstract

Phthalates are industrial plasticizers and stabilizers commonly found in polyvinyl chloride plastic and consumer products, including food packaging, cosmetics, medical devices, and children s toys. Di-(2-ethylhexyl) phthalate (DEHP), one of the most commonly used phthalates, exhibits endocrine-disrupting characteristics and direct exposure leads to reproductive deficits and abnormalities in anxiety-related behaviors. Importantly, increasing evidence indicates that the impacts of DEHP exposure on reproduction and social behavior persist across multiple generations. In this study, we tested the hypothesis that transgenerational DEHP exposure alters anxiety-like behavior and neural gene expression in both male and female mice. Pregnant CD-1 mice were orally dosed daily with either tocopherol-stripped corn oil or DEHP (20 or 200\u202fμg/kg/day; 500 or 750\u202fmg/kg/day) from gestational day 10.5 until birth to produce the F1 generation. Females from each generation were bred with untreated, unrelated CD-1 males to produce subsequent generations. Behavior and gene expression assays were performed with adult, intact F3 males and females. Transgenerational DEHP exposure increased time spent in the open arm in the elevated plus maze for adult females (750\u202fmg/kg/day lineage), but not males. In adult females, we observed a down-regulation of mRNA expression of estrogen receptor 1 in the 200\u202fμg/kg/day and 500\u202fmg/kg/day treatment lineages, mineralocorticoid receptor in the 200\u202fμg/kg/day lineage, and dopamine receptor 2 in the 20\u202fμg/kg/day and 750\u202fmg/kg/day lineages. In adult males, we found an up-regulation of estrogen receptor 2 in the 20 and 200\u202fμg/kg/day lineages, and dopamine receptor 1 in the 20\u202fμg/kg/day and 750\u202fmg/kg/day lineages. No hippocampal gene expression modifications were observed in response to treatment. These results implicate dose-specific transgenerational effects on behavior and neural gene expression in adult male and female mice.