Prenatal Exposure to Propionic Acid and Lipopolysaccharide Produces Developmental Delay, Anxiety-Like Behavior, and Hyper-Sensitivity to Acoustic Startle in Adolescent Rats

Background: The etiology of autism spectrum disorders (ASD) is unknown, with genetic susceptibility interacting with environmental agents. Potential risk factors for ASD include prenatal exposure to medications (ie. valproate, thalidomide) or infections during the first trimester of pregnancy. Gastrointestinal (GI) system influences may contribute to the development of ASD as a subset of patients with ASD exhibit GI symptoms, with abnormal bacterial flora present in the GI tract of children. Propionic acid (PPA) is a short chain fatty acid, structurally related to valproate, and an enteric bacterial fermentation product, including opportunistic ASD associated bacteria such as Clostridia and Desulfovibrio.

Objectives: We have previously found that intracerebroventricular PPA infusion in adult and juvenile rats produces behavioral (hyperactivity, repetitive movements, impaired social interaction) and brain changes (neuroinflammation, oxidative stress, altered lipids) similar to those seen in ASD patients. The present work extended the PPA model to developing rats, examining alterations in behavior due to prenatal exposure to environmental agents.

Methods: Pregnant Long-Evans rats were injected once/day SC with PPA (500 mg/kg; G12-16), lipopolysaccharide (LPS, 50 µg/kg; G15-16) or phosphate buffered saline vehicle (G12-16 or G15-16). Pups were monitored for developmental milestones and assessed in multiple behavioral paradigms in adolescence (drug-free state), including open-field, startle response, and social interaction.

Results: Pups exposed to PPA or LPS prenatally displayed developmental delay compared to vehicle treated pups (ie. pinna detachment, eye opening, incisor eruption). Hypersensitivity to acoustic startle, in the absence of prepulse inhibition deficits, was found in offspring prenatally exposed to either LPS or PPA. In an open-field, prenatally exposed PPA animals spent more time in the perimeter and while in the perimeter, travelled a greater distance than the LPS animals. Preliminary results suggest that offspring of treated dams also showed significant social impairment, avoiding conspecific animals in an open-field.

Conclusions: These results provide further support for the hypothesis that PPA and immune stimulation may be environmental factors contributing to the development of some forms of ASD. Ongoing work assessing the effects of prenatal PPA on brain neuroinflammation and lipid changes will add to the present behavioral evidence.