Perinatal exposure to 50 ppb sodium arsenate induces hypothalamic-pituitary-adrenal axis dysregulation in male C57BL/6 mice

Abstract

Over the past two decades, key advancements have been made in understanding the complex pathology that occurs following not only high levels of arsenic exposure (>1ppm) but also levels previously considered to be low (<100 ppb). Past studies have characterized the deleterious effects of arsenic on the various functions of cardiovascular, pulmonary, immunological, respiratory, endocrine and neurological systems. Other research has demonstrated an elevated risk of a multitude of cancers and increased rates of psychopathology, even at very low levels of arsenic exposure. The hypothalamic-pituitary-adrenal (HPA) axis represents a multisite integration center that regulates a wide scope of biological and physiological processes: breakdown within this system can generate an array of far-reaching effects, making it an intriguing candidate for arsenic-mediated damage. Using a mouse model, we examined the effects of perinatal exposure to 50 ppb sodium arsenate on the functioning of the HPA axis through the assessment of corticotrophin-releasing factor (CRF), proopiomelanocortin (Pomc) mRNA, adrenocorticotrophin hormone (ACTH), corticosterone (CORT), 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD 1), and glucocorticoid receptor (GR) protein and mRNA. Compared to controls, we observed that the perinatal arsenic-exposed offspring exhibit an increase in hypothalamic CRF, altered CORT secretion both at baseline and in response to a stressor, decreased hippocampal 11β-HSD 1 and altered subcellular GR distribution in the hypothalamus. These data indicate significant HPA axis impairment at post-natal day 35 resulting from perinatal exposure to 50 ppb sodium arsenate. Our findings suggest that the dysregulation of this critical regulatory axis could underlie important molecular and cognitive pathology observed following exposure to arsenic.

Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism

“…We have previously demonstrated that arsenic-exposed mice fail to activate a normal corticosterone (CORT) response to TMT (Goggin et al, 2012); to determine if fluoxetine attenuates this effect, CORT levels at baseline and after TMT exposure were determined in all animals. As seen in Fig.…”

“…Additionally, HPA axis stress responses in the dentate gyrus are mediated in part through the glucocorticoid receptor (GR) and can impact gene expression (de Kloet et al, 2005). For its part, arsenic exposure induces deficits in mRNA expression of neurogenesis-related genes, including Nrc31 (gene for GR protein), Creb1 , and Hdac2 (Goggin et al, 2012; Tyler and Allan, 2013), though the mechanism by which this damage occurs is unclear. Thus to determine the pathways involved in fluoxetine’s neurogenic actions and in arsenic-induced morphological damage, we assessed expression of proteins involved in AHN, including the GR, CREB, HDAC2, and BDNF.…”

“…Exposure to 2,3,5-trimethyl-3-thiazoline (TMT) (Contech, Victoria, BC, Canada; #300000368) was performed as previously described (Goggin et al, 2012). Animals were individually transferred to an exposure cage containing filter paper saturated with 100 μL of 3% (v/v) TMT for 10 min.…”

“…Individuals with robust homeostatic responses to stress are often considered resistant to depression (Krishnan and Nestler, 2008), thus dysregulation of the HPA axis after toxin exposure may be a mechanism by which toxins, like arsenic, increase susceptibility to psychiatric disorders. Indeed, we have previously demonstrated that perinatal (pre- and postnatal developmental) arsenic exposure (PAE) alters glucocorticoid signaling within the HPA axis, blunts stress responses, increases stress reactivity (Goggin et al, 2012), and results in depressive-like behavior in adulthood (Martinez et al, 2008; Martinez-Finley et al, 2009). In addition to these aberrations, we have also observed altered hippocampal morphology and deficits in adult hippocampal neurogenesis after PAE (Tyler and Allan, 2013).…”

Inorganic Arsenic Exposure and Children’s Neurodevelopment: A Review of the Evidence

“…These mechanisms, identified in experimental animal studies, include oxidative stress and the production of free radicals resulting in neuronal apoptosis [12,13], impaired hippocampal neurogenesis [14], dysregulation of the hypothalamo-pituitary-adrenal axis including reduced levels of corticosterone receptors in the hippocampus [15,16], epigenetic effects such as reduced DNA methylation in the hippocampus and frontal cortex [17], reductions in brain levels of biogenic amines and other neurotransmitters [18][19][20][21], changes in the expression of the NMDA receptor complex [22], inhibition of neurite outgrowth [23], structural malformation of white matter (e.g., myelin sheaths) [24] and of hippocampal mossy fibers [25], and endocrine disruption, including down-regulation of thyroid hormone receptor genes [26,27].…”