title: Direct and transgenerational effects of low doses of perinatal di-(2-ethylhexyl) phthalate (DEHP) on social behaviors in mice.
abstract: Di-(2-ethylhexyl) phthalate (DEHP) is an endocrine disrupting chemical commonly used as a plasticizer in medical equipment, food packaging, flooring, and children's toys. DEHP exposure during early development has been associated with adverse neurobehavioral outcomes in children. In animal models, early exposure to DEHP results in abnormal development of the reproductive system as well as altered behavior and neurodevelopment. Based on these data, we hypothesized that developmental exposure to DEHP would decrease social interactions and increase anxiety-like behaviors in mice in a dose-dependent manner, and that the effects would persist over generations. C57BL/6J mice consumed one of three DEHP doses (0, 5, 40, and 400 μg/kg body weight) throughout pregnancy and during the first ten days of lactation. The two higher doses yielded detectable levels of DEHP metabolites in serum. Pairs of mice from control, low, and high DEHP doses were bred to create three dose lineages in the third generation (F3). Average anogenital index (AGI: anogenital distance/body weight) was decreased in F1 males exposed to the low dose of DEHP and in F1 females exposed to the highest dose. In F1 mice, juvenile pairs from the two highest DEHP dose groups displayed fewer socially investigative behaviors and more exploratory behaviors as compared with control mice. The effect of DEHP on these behaviors was reversed in F3 mice as compared with F1 mice. F1 mice exposed to low and medium DEHP doses spent more time in the closed arms of the elevated plus maze than controls, indicating increased anxiety-like behavior. The generation-dependent effects on behavior and AGI suggest complex mechanisms by which DEHP directly impacts reproductive and neurobehavioral development and influences germline-inherited traits.
authors.affiliation: Department of Biochemistry and Molecular Genetics and Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, VA, United States of America.
authors.forename: Kayla M
authors.initials: KM
authors.lastname: Quinnies
authors.affiliation: Department of Biochemistry and Molecular Genetics and Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, VA, United States of America.
authors.forename: Erin P
authors.initials: EP
authors.lastname: Harris
authors.affiliation: Discovery Science Technology, RTI International, Research Triangle Park, NC, United States of America.
authors.forename: Rodney W
authors.initials: RW
authors.lastname: Snyder
authors.affiliation: Discovery Science Technology, RTI International, Research Triangle Park, NC, United States of America.|Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, United States of America.
authors.forename: Susan S
authors.initials: SS
authors.lastname: Sumner
authors.affiliation: Department of Biochemistry and Molecular Genetics and Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, VA, United States of America.|Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, United States of America.
authors.forename: Emilie F
authors.initials: EF
authors.lastname: Rissman
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004051:Diethylhexyl Phthalate / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D008297:Male; D018811:Maternal Exposure; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012919:Social Behavior
chemical_list: D004051:Diethylhexyl Phthalate