Effects of Endocrine Disruption and Immune Status on Social Behavior.

Many factors affect behavior and development. Two important examples are immune system function and chemicals in the environment. Endocrine disrupting chemicals are abundant and affect behavior, hormone levels, reproduction, and neurodevelopment. One such chemical, di-(2-ethylhexyl) phthalate (DEHP), is used in hospital equipment, food packaging, flooring, and children’s toys. Dose response studies show a non-monotonic response where measurable outcomes do not linearly map to increased exposure. The central hypothesis of this dissertation is that DEHP affects estradiol and testosterone during development that impact social and anxiety behavior and reproductive development in a dose-dependent manner, and that this early exposure has effects several generations later. I evaluated this in two studies. The first used antiandrogenic doses (150mg/kg and 200mg/kg) comparable to a dose that causes transgenerational changes in sperm. DEHP was administered to dams during a gestational window where DNA demethylation and remethlyation and important neurodevelopment occur. The mice that I studied were third generation offspring removed from contact with DEHP. Females from the DEHP-lineage had lower serum corticosterone following restraint stress, and DEHP-lineage males had altered social behavior and reproductive development. The second project was a dose response study with a range of human relevant doses that I hypothesized would be androgenic (5, 40, and 400 μg/kg) administered during gestation and a portion of lactation to imitate human exposure. There were dose and sex-specific outcomes on social and anxiety behavior and reproductive development following direct exposure, as well as increased social behavior several generations later. I also hypothesized that developmental immune deficiency would affect social behavior based on known effects on learning in mice and correlation with behavioral disorders in human. A study using a mouse model of severe combined immunodeficiency (SCID) resulted in impaired social recognition in juveniles that was rescued by transfer of healthy splenocytes. SCID mice also had decreased maternal behavior, which affected social preference in offspring.