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

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.

Anxiolytic and anti-inflammatory role of thymoquinone in arsenic-induced hippocampal toxicity in Wistar rats

“…Earlier studies on chronic inorganic arsenic exposure in rodents revealed that it causes behavioral ( BonakdarYazdi et al., 2017 ; Jing et al., 2012 ), morphological ( Ríos et al., 2009 ), physiological, ( Arslan-Acaroz et al., 2018 ) and neurochemical ( Yadav et al., 2011 ) effects. Recent studies have also supported the neurodevelopmental toxicity associated with arsenic exposure ( Aung et al., 2016 ; Sidhu et al., 2006 ). Similar doses of inorganic arsenic have also shown toxic effect on organs like liver and kidney that reported increased generation of reactive oxygen species and histopathological changes ( Bali et al., 2016 ; Noman et al., 2015 ).…”

Effects of Developmental Arsenic Exposure on the Social Behavior and Related Gene Expression in C3H Adult Male Mice

“…The weight of water bottle for each mouse was measured before and after providing ad libitum access to water. The reasons for selection of a 85 ppm dose of NaAsO 2 are: (1) species differences were observed between human and mouse and a high dose is required for detection of neurotoxic effects in C3H mice and no maternal toxicity and teratogenicity were observed at the dose of present study; (2) this is a standard dose to detect the effects of developmental exposure to arsenic on neurotoxicity, reproductive toxicity and carcinogenicity in our research group [22,32,33]. The F1 male pups were weaned at postnatal day 21 and were randomly selected from different dams and housed under the same condition as the dams ( n = 3 per cage).…”

“…The previous study showed that behavioral inflexibility and cortical disarrangement in the prelimbic cortex was observed in 60-week-old C3H male mice after prenatal exposure to 85 ppm arsenic [22]. This finding prompted us to examine social behavior after the same exposure period (GD 8 to 18).…”

“…They believed that the lack of differentiated neural progenitor cells necessary for hippocampal-dependent learning leads to behavioral deficits observed during adulthood [21]. Aung et al demonstrated that prenatal arsenic exposure leads to behavioral inflexibility to changing tasks in adulthood and cortical disarrangement in the prelimbic cortex in C3H mice [22].…”

Tumor-augmenting effects of gestational arsenic exposure on F1 and F2 in mice

“…Furthermore, gestational exposures to a variety of environmental factors, including several chemicals, have been reported to cause not only multigenerational (in F1 and F2), but also transgenerational effects that are inherited by the F3 and following generations [ 14 , 15 ]. In addition to the tumor augmenting effects, we recently demonstrated that arsenic exposure of pregnant mice causes behavioral inflexibility and impaired cortical structure in the F1 offspring [ 51 ]. A recent study by another group reported that arsenic exposure of pregnant mice leads to obesity and early onset of the vaginal opening in the F1 females [ 52 ].…”