Gender specific changes in key regulators of neurodevelopment and autistic behavioral pathology in mice exposed to water chlorination byproducts

Autism is a heterogeneous group of disorders with no definitive etiology. Out of concern for higher than expected prevalence, the Agency for Toxic Substances and Disease Registry (ATSDR) investigated the municipal water supply in Brick Township, New Jersey. The ATSDR found that two trihalomethanes (THMs), specifically chloroform and bromoform, as well as tetrachloroethylene (perchlorethylene; PCE), were present in concentrations that exceeded allowable maximum contaminant (MCL) values. In a related study, it was found that THMs and PCE act synergistically to increase the level of catalytic Protein Kinase A (PKA) in neurons of clam embryos. PKA is a key regulator of neurodevelopment, and it is hypothesized that abnormalities in PKA activity could induce both histopathological and biochemical manifestations that are found in autism. Based upon these findings, we hypothesized that THM/PCE exposure induces changes in key regulators of neurodevelopment and behavioral pathology similar to that which is found in autism. In our experiments we found that exposure to THM/PCE induces an increase in the level of catalytically active PKA in zebrafish neurons and increases PKA activity in microglia cell culture. In a mouse model, we found that exposure to THM/PCE via drinking water induces an increase in the activity of PKA in the cerebral cortex of male animals at postnatal day 4 (P4) and postnatal day 10 (P10). Females cortical PKA activity was unaffected by THM/PCE exposure. By P15, male cortical PKA activity is no longer affected by THM/PCE exposure and female cortical PKA activity remains unaffected. Behaviorally, we found that the THM/PCE exposed males develop autistic like behavioral pathology as they evidence deficits in communication and social behavior and demonstrate both perseverance behavior and anxiety. Again, this finding is gender specific, as female behavior is unaffected by THM/PCE exposure. These findings suggest that these chemicals may be involved in the etiology of autism and that males are more susceptible to this set of insults.