Prenatal Exposure to Group B Streptoccocus, Phthalates, and Flame Retardants: A New Animal Model for ASD?

Background: Epidemiological data suggests that: (i) prenatal exposure to phthalates and flame retardants (FRs) can affect mental and motor development, and provoke internalizing behavior; (ii) there is a clear link between ASD and prematurity, frequently associated with chorioamnionitis, for which Group B Streptoccocus (GBS) is one of the most frequent causes. We hypothesize that the combination of these two frequent aggressions (GBS and FRs/phthalates) during a critical perinatal period can lead to ASD through a perinatal neuroinflammatory response. In numerous rodent studies, valproic acid, a frequently prescribed antiepileptic drug, has been shown to induce ASD-like behavior including lower exploratory activity, deficit in social behaviors, diminished acoustic prepulse inhibition, delayed nest-seeking response. We therefore used valproic acid as a positive control in our study.

Objectives: To determine the extent to which prenatal exposure to GBS and/or phthalates/FRs induces the full spectrum of autism relevant behavior.

Methods: The study was carried out in 25 pregnant Lewis rats exposed to:

  GROUP 1: a mixture of selected  FRs and phthalates at low dose (3 phthalate : DEHP, DBP, DiNP; and 2 FRs : BDE-47, BDE-99) (n=7) in peanut oil by gavage from GD15 to delivery;

  GROUP 2: inactivated GBS by i.p. injections from GD19 to GD22 and the same mixture of contaminants as in GROUP 1 (n=7) by gavage

  GROUP 3: 600mg/kg of valproic acid by i.p. injection at GD12, a positive control group (n=5);

  GROUP 4: peanut oil vehicle by gavage from GD15 to delivery (n=6), a negative control group.

The following behavioral tests were administered to offspring: recording of ultrasonic vocalizations (PND7 and PND14), nest-seeking behavior (PND8), auditory startle (PND11 to PND13), Open Field (PND20), Elevated Plus Maze (PND25), prepulse inhibition (PPI) of the acoustic startle (PND35), and test of social interactions (PND40). 

Results: Our preliminary results show that offspring exposed to GBS and contaminants, as well as those exposed to valproic acid, showed significantly more difficulty to find the maternal compartment in nest-seeking behavior and were less active in the Open Field test than control animals. Animals exposed in utero to the mixture of FRs and phthalates were more active in the Open Field and social interactions tests.

In addition, we observed a dramatic effect of valproate acid on gestation in 3 of the 5 dams (non delivery and spots of embryo implantation on the uterus) and on developmental landmarks (decreased birth weight, delayed eye opening and fur growth) in the 2 delivered litters.

Conclusions: Our results suggest that simultaneous prenatal exposure to GBS, phthalates, and FRs induces long term behavioral effects in rat offspring, similar to the features of ASD, including a very attenuated response to maternal presence and substantially less explorative behavior.