Prenatal Exposure to Arsenic Impairs Behavioral Flexibility and Cortical Structure in Mice.

Kyaw H Aung,Masaki Kakeyama,Keiko Nohara,Chiharu Tohyama,Kazuhiro Sano,Akito Tanoue,Fumihiko Maekawa,Shinji Tsukahara,Chaw Kyi-Tha-Thu,Kazuaki Nakamura

doi:10.3389/fnins.2016.00137

Abstract

Exposure to arsenic from well water in developing countries is suspected to cause developmental neurotoxicity. Although, it has been demonstrated that exposure to sodium arsenite (NaAsO2) suppresses neurite outgrowth of cortical neurons in vitro, it is largely unknown how developmental exposure to NaAsO2 impairs higher brain function and affects cortical histology. Here, we investigated the effect of prenatal NaAsO2 exposure on the behavior of mice in adulthood, and evaluated histological changes in the prelimbic cortex (PrL), which is a part of the medial prefrontal cortex that is critically involved in cognition. Drinking water with or without NaAsO2 (85 ppm) was provided to pregnant C3H mice from gestational days 8 to 18, and offspring of both sexes were subjected to cognitive behavioral analyses at 60 weeks of age. The brains of female offspring were subsequently harvested and used for morphometrical analyses. We found that both male and female mice prenatally exposed to NaAsO2 displayed an impaired adaptation to repetitive reversal tasks. In morphometrical analyses of Nissl- or Golgi-stained tissue sections, we found that NaAsO2 exposure was associated with a significant increase in the number of pyramidal neurons in layers V and VI of the PrL, but not other layers of the PrL. More strikingly, prenatal NaAsO2 exposure was associated with a significant decrease in neurite length but not dendrite spine density in all layers of the PrL. Taken together, our results indicate that prenatal exposure to NaAsO2 leads to behavioral inflexibility in adulthood and cortical disarrangement in the PrL might contribute to this behavioral impairment.

Highlights

The developing brain is vulnerable to disruption by environmental factors including toxic chemical exposure
While the discrimination error rate of both the control and NaAsO2-exposed males was significantly decreased to approximately 10% by session 11 (Figure S4), the discrimination error rate of both groups of females was decreased to approximately 15% by session 21 (Figure 1E)
We investigated the effect of prenatal NaAsO2 exposure on the behavioral flexibility/reversal learning of adult mice using the IntelliCage system, which is an efficient tool for monitoring multiple aspects of cognitive behavior in a social environment (Endo et al, 2012; Benner et al, 2015)

Summary

Introduction

The developing brain is vulnerable to disruption by environmental factors including toxic chemical exposure. Exposure to inorganic lead, methylmercury, and polychlorinated biphenyls during gestation and early childhood are associated with the prevalence of mental retardation, cerebral palsy, and ADHD in children (Grandjean and Landrigan, 2006; Bisen-Hersh et al, 2014) These studies indicate that early life environmental exposures play a role in the etiology of neurodevelopmental disorders. Follow-up studies on victims of arsenic poisoning from the Morinaga formula incident in Japan revealed an association between oral exposure to arsenic during infancy and various brain disorders, including mental retardation and epilepsy (Dakeishi et al, 2006) These studies suggest that early life arsenic exposure can affect higher brain function later in life. Few behavioral deficits such as an increase in pivoting, a type of abnormal gait behavior, was observed in younger mouse offspring following a short period of gestational exposure to arsenic (Colomina et al, 1996)

Methods

Results

Conclusion