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. 2008 Jul;29(4):647-55.
doi: 10.1016/j.neuro.2008.05.004. Epub 2008 May 21.

Moderate perinatal arsenic exposure alters neuroendocrine markers associated with depression and increases depressive-like behaviors in adult mouse offspring

Ebany J Martinez  1 , Bethany L Kolb, Angela Bell, Daniel D Savage, Andrea M Allan
Affiliations

Moderate perinatal arsenic exposure alters neuroendocrine markers associated with depression and increases depressive-like behaviors in adult mouse offspring

Ebany J Martinez et al. Neurotoxicology. 2008 Jul.

Abstract

Arsenic is one of the most common heavy metal contaminants found in the environment, particularly in water. We examined the impact of perinatal exposure to relatively low levels of arsenic (50 parts per billion, ppb) on neuroendocrine markers associated with depression and depressive-like behaviors in affected adult C57BL/6J mouse offspring. Whereas most biomedical research on arsenic has focused on its carcinogenic potential, a few studies suggest that arsenic can adversely affect brain development and neural function. Compared to controls, offspring exposed to 50 parts per billion arsenic during the perinatal period had significantly elevated serum corticosterone levels, reduced whole hippocampal CRFR 1 protein level and elevated dorsal hippocampal serotonin 5HT 1A receptor binding and receptor-effector coupling. 5HT 1A receptor binding and receptor-effector coupling were not different in the ventral hippocampal formation, entorhinal or parietal cortices, or inferior colliculus. Perinatal arsenic exposure also significantly increased learned helplessness and measures of immobility in a forced swim task. Taken together, these results suggest that perinatal arsenic exposure may disrupt the regulatory interactions between the hypothalamic-pituitary-adrenal axis and the serotonergic system in the dorsal hippocampal formation in a manner that predisposes affected offspring to depressive-like behavior. These results are the first to demonstrate that relatively low levels of arsenic exposure during development can have long-lasting adverse effects on behavior and neurobiological markers associated with these behavioral changes.

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Figures

Figure 1
Figure 1
The effect of perinatal arsenic exposure on plasma corticosterone levels. Data bars represent the mean ± SEM nanograms corticosterone per mL plasma from five or six mice per perinatal treatment group. Asterisk denotes data significantly elevated compared to the control water group (two-tailed t-test, t(9) = 2.491, p = 0.03).
Figure 2
Figure 2
The effect of perinatal arsenic exposure on hippocampal CRF receptor protein levels in adult offspring. A: Representative immunoblots of triplicate control and arsenic-exposed samples and a standard curve. B: Data expressed as immunoreactivity units calculated from a protein standard curve using control hippocampal tissue. Data bars represent the mean ± SEM of 12 mice in each perinatal treatment group. Beta-actin was used as a loading control. Asterisk denotes data significantly different compared to the control water group (t (22) = 3.64, p<0.001).
Figure 3
Figure 3
Autoradiograms of [3H]-DPAT binding and DPAT-stimulated [35S]-GTPγS binding in coronal sections of brain from an untreated control mouse. A: Total [3H]-DPAT binding. B: Non-specific [3H]-DPAT binding (binding in the presence of 20 µM unlabelled DPAT). C: [35S]-GTPγS binding in the presence of 2 µM DPAT. D: Basal [35S]-GTPγS binding (binding in the absence of added DPAT). Binding measurements were made in the dorsal hippocampal CA1 stratum radiatum and the parietal cortex (Layers 1–3) immediately dorsal to the hippocampal formation. The horizontal bar at the bottom of panel D denotes a distance of 1 mm.
Figure 4
Figure 4
Autoradiograms of [3H]-DPAT binding and DPAT-stimulated [35S]-GTPγS binding in horizontal sections of brain from an untreated control mouse. A: Total [3H]-DPAT binding. B: Nonspecific [3H]-DPAT binding (binding in the presence of 20 µM unlabelled DPAT). C: [35S]-GTPγS binding in the presence of 2 µM DPAT. D: Basal [35S]-GTPγS binding (in the absence of added DPAT). Binding measurements were made in the ventral hippocampal CA1 stratum radiatum, medial entorhinal cortex, (Layers 1–3) and the inferior colliculus. The horizontal bar at the bottom of panel D denotes a distance of 1 mm.
Figure 5
Figure 5
The effects of perinatal arsenic exposure on 5HT1A receptor density and 5HT1A receptor-effector coupling in five regions of adult mouse brain. A: Specific [3H]-DPAT binding. B: Basal [35S]-GTPγS binding. C: 2 µM DPAT-stimulated [35S]-GTPγS binding. D: 20 µM DPAT-stimulated [35S]-GTPγS binding. Data bars represent the mean ± SEM of 5 to 11 mice in each group. Asterisks denote data significantly increased compared to the untreated control group (multivariate, one-way ANOVA F(1,12)=9.8 p<0.001 in Figure 5A; F(1,10)=6.6 p<0.03 in Figure 5C).
Figure 6
Figure 6
The effect of perinatal arsenic exposure on learned helplessness in adult male and female offspring. Data bars represent the mean ± the SEM of five mice in each group. Asterisks denote significant differences between control and arsenic-exposed offspring. A two-way ANOVA was performed with a t-test as a post-hoc. There was a significant effect of perinatal arsenic F(1,20) = 81.85 p<0.0001. There was no effect of gender F(1,20)= 3.043 p=0.096 (not significant) and no interaction between perinatal treatment and gender in learned helplessness training F(1,20)= 0.012 p=0.913, not significant.
Figure 7
Figure 7
The effect of perinatal arsenic exposure on forced swim task in adult offspring. Data bars represent the mean ± the SEM of eight mice in each group. Asterisks denote a significant elevation in time spent in immobile behaviors compared to the control water group (two-tailed t-test, t(14) = 8.11, p < 0.001).
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