Elsevier

NeuroToxicology

Volume 29, Issue 2, March 2008, Pages 318-327
NeuroToxicology

The common environmental pollutant dioxin-induced memory deficits by altering estrogen pathways and a major route of retinol transport involving transthyretin

https://doi.org/10.1016/j.neuro.2007.12.005Get rights and content

Abstract

Many toxic environmental and food agents have been suspected to be potential risk factors in inducing memory disabilities under normal and pathological conditions. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (known as dioxin or TCDD) is a common and prototypical member of a class of noxious environmental and food contaminants called the halogenated aromatic hydrocarbons. Since the role of dioxin in memory processes has not been studied in detail, the present report aims at elucidating the role of this pollutant in the maintenance of cognitive function. We found that TCDD (50 μg/kg) induced spatial memory deficits in the Morris water maze (MWM) task in female but not male mice. This sex-dependant effect of dioxin seems to be related to the alteration of estrogen pathways, as treatment with 17β-estradiol-3-benzoate (E; 5 μg/day) reversed memory deficits induced by TCDD. We also observed that cognitive impairments produced by dioxin, which is known to interfere with retinoid turnover and metabolism, were abolished by retinoic acid (RA) treatment (150 μg/kg). The cognitive effects of E and RA treatments seem to derive from common rather than additive mechanisms since memory deficits produced by TCDD were fully reversed by these compounds when used separately or in combination. Attenuation of dioxin-induced memory deficits in mice lacking transthyretin (TTR) suggests that TCDD may be acting by affecting the major route of retinol transport involving TTR. Taken together, these results suggest that the environmental and food pollutant TCDD can induce memory deficits by altering the estrogen pathways and a main route of TTR-mediated retinol transport.

Introduction

According to the World Health Organization, dioxin is a widespread toxic environmental and food contaminant. This highly noxious agent is present in air, water and soil mainly because of pollution generated by industrialized societies such as large-scale burning of municipal and medical waste, fuel and wood burning, tobacco smoke, production of iron and steel, bleaching process of paper pulp, coal-fired electric power generation and pesticides. This prototypical member of the halogenated aromatic hydrocarbons (HAHs) can also move into food chain and contaminate meat, milk products (including breast milk) as well as fish and to a lower level fruits, vegetables and grains. Since dioxin is stored in body fat, its half-life is very long (around 7–8 years in adult humans) and thus can accumulate in the organism over time (Pohjanvirta et al., 1990). The acute toxicity of TCDD in humans was shown to be in the range of 70–300 μg/kg, with 10 ρg/(kg day) representing a safe lifetime exposure level (Rozman, 1989). Several industrial accidents or natural disasters such as forest fires and volcanic eruptions have exposed many individuals to high levels of TCDD and other HAHs. It has been established that most of the effects exerted by TCDD and other HAHs are mediated through binding to the nuclear arylhydrocarbon receptor (AhR), which in turn increases or decreases the expression of AhR-regulated genes (Schmidt and Bradfield, 1996).

A few evidences suggest that this common noxious pollutant may alter memory capacities. Electrophysiological data have shown that TCDD represses excitatory post-synaptic potentials (EPSPs) in rat hippocampal slices (Hong et al., 1998). Air force veterans highly exposed to Agent Orange containing TCDD during the Vietnam War show deficits in several measures of memory functioning (Michalek et al., 2001). Long-term cognitive deficits have been reported following prenatal exposure to low levels of TCDD in monkeys (Schantz and Bowman, 1989) and rats (Powers et al., 2005, Seo et al., 1999). However, memory deficits in adult animals administered with TCDD remains to be investigated.

The mechanisms underlying the effect of this toxic agent on cognitive processes are also mostly unknown. A close association between disturbances in vitamin A (retinol) homeostasis and toxicity of dioxin was first proposed on the basis of similar symptoms seen in hypovitaminosis A and TCDD-exposed animals (Thunberg et al., 1980). Various studies have reported that TCDD interferes with retinoid turnover and metabolism by increasing retinoid mobilization from retinyl ester stores (Brouwer et al., 1989, Jurek et al., 1990, Kelley et al., 2000, Van Birgelen et al., 1995), altering retinol esterification (Hoegberg et al., 2003, Nilsson et al., 2000), changing tissue levels of retinoic acid (Hoegberg et al., 2003, Kelley et al., 1998, Nilsson et al., 2000), augmenting whole body turnover of retinoids (Kelley et al., 1998), and increasing excretion of retinoid metabolites (Brouwer et al., 1989, Hakansson and Ahlborg, 1985).

Retinol is stored in the liver as retinyl ester and secreted into the circulation bound to its specific transport protein, retinol-binding protein (RBP) in response to physiological needs. Retinol bound to RBP secreted by the liver represents 95–99% of the vitamin A present in the circulation. This binary complex binds to the plasma protein transthyretin (TTR) to form the major retinol transport route from its storage in the liver to target tissues. TTR was shown to prevent renal glomerular filtration and influence secretion of the retinal–RBP complex from the liver (Monaco, 2000). Once delivered to the target organs, retinol is metabolized into retinoic acid (RA) which acts on specific nuclear receptors to modulate a wide variety of biological processes including synaptic plasticity (Misner et al., 2001), neurogenesis (Jacobs et al., 2006, Snyder et al., 2005) as well as long-term potentiation (LTP) and long-term depression (LTD), two synaptic models of memory (Chiang et al., 1998, Etchamendy et al., 2001). The hypothesis that TCDD-induced memory deficits could be associated to its capacities to altered retinol metabolism by acting on its delivery route has yet to be investigated.

Several studies have reported that some effects of dioxin are sex-dependant and may occur through the inhibition of estrogen signalling pathways (Safe et al., 2000, Tritscher et al., 1996, Wormke et al., 2000, Wyde et al., 2001). Considerable evidence suggest that estrogen is not only involved in reproduction but also in other neural mechanisms such as learning and memory (Sherwin, 1994). Estrogen receptors are widely distributed in the hippocampus and other brain areas implicated in memory processing (Hart et al., 2001, Shughrue et al., 1997, Shughrue and Merchenthaler, 2000). Electrophysiological data have shown that estrogen increases LTP and N-methyl-d-aspartate (NMDA)-mediated EPSPs, whereas it can attenuate the inhibition mediated by gamma-aminobutyric acid (GABA) (Cordoba Montoya and Carrer, 1997, Gureviciene et al., 2003, Rudick and Woolley, 2001). Although results from behavioural studies investigating the role of estrogen in the maintenance or improvement of memory capacities are somewhat controversial, evidence suggests that estrogen administered to young ovariectomized as well as aged female rodents can enhance spatial and non-spatial learning and memory (Frick et al., 2002, Gibbs, 1999, Packard and Teather, 1997, Rissanen et al., 1999, Sandstrom and Williams, 2001, Vaucher et al., 2002; but also Chesler and Juraska, 2000, Fugger et al., 1998). However, it remains to be established if dioxin can interact with estrogen pathways to alter cognitive abilities.

The present study investigates the potential role of TCDD on learning abilities and potential mechanisms relevant to this effect. We observed that TCDD induced robust memory impairments in the Morris water maze (MWM) task in female but not male mice. These deficits were abolished by treatment with 17β-estradiol-3-benzoate (E) and/or RA. Furthermore, a decrease of TCDD-induced memory deficits in TTR knock-out (TTR−/−) mice suggest that this agent acts on a major route of TTR-mediated retinol transport to alter memory functions.

Section snippets

Animals

Wild-type (WT; n = 77) and TTR−/− mice (n = 14; F2 generation maintained on a mixed C57BL/6 × 129S background) were purchased from The Jackson Laboratory (Bar Harbor, ME, USA). Animals were housed in groups of maximum four per cage and maintained on a 12-h light/dark cycle with ad libitum access to food and water. The mice were bred in our animal facility and behavioural testing was started at 3-month of age. Animal care and handling procedures were approved by the McGill University Animal Care

TCDD-induced memory deficits in MWM task

Female and male (3-month old) mice treated 72 h prior to MWM training with a single dose of TCDD (50 μg/kg, ip) and control animals treated with corn oil (vehicle) were tested in the reference memory version of the MWM task, where the hidden escape platform stayed at the same location during all training days (Fig. 1A and B). The two-way, one between, one within ANOVA conducted on the mean escape latencies of female mice yielded a significant group × days interaction (F4,48 = 3.62; p < 0.0117). Simple

Discussion

Normal cognitive functions can be altered by noxious pollutants from the environment and food. Studies on the deleterious mnemonic effects of TCDD, a prototypical member of the highly toxic HAHs, could reveal mechanisms through which this class of widespread environmental contaminants affect learning and memory processes. Our report provides behavioural and pharmacological evidence that TCDD induces severe memory deficits in female but not male mice. This gender-specific effect of TCDD on

Acknowledgments

This work was supported by grants from the Canadian Institutes of Health Research (CIHR) to R.Q. and a studentship award from CIHR to J.B. We also thank Mira Thakur for correcting this paper.

References (72)

  • K.M. Frick et al.

    Estrogen replacement improves spatial reference memory and increases hippocampal synaptophysin in aged female mice

    Neuroscience

    (2002)
  • H.N. Fugger et al.

    Sex differences in the activational effect of ERalpha on spatial learning

    Horm Behav

    (1998)
  • R.B. Gibbs

    Estrogen replacement enhances acquisition of a spatial memory task and reduces deficits associated with hippocampal muscarinic receptor inhibition

    Horm Behav

    (1999)
  • I. Gureviciene et al.

    Estrogen treatment alleviates NMDA-antagonist induced hippocampal LTP blockade and cognitive deficits in ovariectomized mice

    Neurobiol Learn Mem

    (2003)
  • H. Hakansson et al.

    The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the uptake, distribution and excretion of a single oral dose of [11,12-3H]retinyl acetate and on the vitamin A status in the rat

    J Nutr

    (1985)
  • P. Hoegberg et al.

    Retinoid status and responsiveness to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking retinoid binding protein or retinoid receptor forms

    Chem Biol Interact

    (2005)
  • P. Hoegberg et al.

    2,3,7,8-Tetrachlorodibenzo-p-dioxin induces lecithin: retinol acyltransferase transcription in the rat kidney

    Chem Biol Interact

    (2003)
  • S.J. Hong et al.

    Halogenated aromatic hydrocarbons suppress CA1 field excitatory postsynaptic potentials in rat hippocampal slices

    Toxicol Appl Pharmacol

    (1998)
  • S.K. Kelley et al.

    Use of model-based compartmental analysis to study effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on vitamin A kinetics in rats

    Toxicol Sci

    (1998)
  • X.H. Li et al.

    Cellular retinoic acid-binding protein II gene expression is directly induced by estrogen, but not retinoic acid, in rat uterus

    J Biol Chem

    (2003)
  • Y. Lu et al.

    Interaction of 2,3,7,8-tetrachlorodibenzo-p-dioxin and retinoic acid in MCF-7 human breast cancer cells

    Toxicol Appl Pharmacol

    (1994)
  • T.A. Mably et al.

    In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin. 2. Effects on sexual behavior and the regulation of luteinizing hormone secretion in adulthood

    Toxicol Appl Pharmacol

    (1992)
  • J.E. Michalek et al.

    Serum dioxin and peripheral neuropathy in veterans of Operation Ranch Hand

    Neurotoxicology

    (2001)
  • H.L. Monaco

    The transthyretin-retinol-binding protein complex

    Biochim Biophys Acta

    (2000)
  • R. Morris

    Developments of a water-maze procedure for studying spatial learning in the rat

    J Neurosci Methods

    (1984)
  • C.B. Nilsson et al.

    2,3,7,8-Tetrachlorodibenzo-p-dioxin increases serum and kidney retinoic acid levels and kidney retinol esterification in the rat

    Toxicol Appl Pharmacol

    (2000)
  • M.G. Packard et al.

    Posttraining estradiol injections enhance memory in ovariectomized rats: cholinergic blockade and synergism

    Neurobiol Learn Mem

    (1997)
  • M. Romkes et al.

    Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on hepatic and uterine estrogen receptor levels in rats

    Toxicol Appl Pharmacol

    (1987)
  • S.H. Safe

    Modulation of gene expression and endocrine response pathways by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds

    Pharmacol Ther

    (1995)
  • S.L. Schantz et al.

    Learning in monkeys exposed perinatally to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

    Neurotoxicol Teratol

    (1989)
  • B.W. Seo et al.

    Learning and memory in rats gestationally and lactationally exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

    Neurotoxicol Teratol

    (1999)
  • P.J. Shughrue et al.

    Estrogen is more than just a “sex hormone”: novel sites for estrogen action in the hippocampus and cerebral cortex

    Front Neuroendocrinol

    (2000)
  • J.S. Snyder et al.

    A role for adult neurogenesis in spatial long-term memory

    Neuroscience

    (2005)
  • P.W. Stewart et al.

    Cognitive development in preschool children prenatally exposed to PCBs and MeHg

    Neurotoxicol Teratol

    (2003)
  • A.S. Thornton et al.

    The dioxin TCDD protects against aflatoxin-induced mutation in female rats, but not in male rats

    Mutat Res

    (2004)
  • A.M. Tritscher et al.

    Increased oxidative DNA damage in livers of 2,3,7,8-tetrachlorodibenzo-p-dioxin treated intact but not ovariectomized rats

    Cancer Lett

    (1996)
  • Cited by (12)

    • Sex-specific enhanced behavioral toxicity induced by maternal exposure to a mixture of low dose endocrine-disrupting chemicals

      2014, NeuroToxicology
      Citation Excerpt :

      Of further note is the report that nearly all AhR gene expression in the brain of developing and adult rats is found in GABAergic neurons (i.e., those expressing the glutamic acid decarboxylase, the enzymes critical for GABA synthesis) suggesting GABA inhibitory function may be a target of TCDD exposure (Hays et al., 2002) which could modulate the dopamine/glutamate balance of mesocorticolimbic systems (Harte and O’Connor, 2005; Yamaguchi et al., 2011). Animal and human studies suggest that exposure to TCDD elicits memory deficits, with some suggestion that females are more susceptible than males (Barrett et al., 2001; Brouillette and Quirion, 2008). PFOA exposed males also showed increased ambulatory movement and decreased resting time, suggesting significantly increased hyperactivity compared to controls.

    • 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces expression of p27<sup>kip1</sup> and FoxO3a in female rat cerebral cortex and PC12 cells

      2014, Toxicology Letters
      Citation Excerpt :

      Previous studies in rats have proved that female rats are more sensitive to TCDD lethality than male ones (Pohjanvirta et al., 1993). A few reports showed that TCDD induced memory deficits in female but not male mice (Powers et al., 2005; Brouillette and Quirion, 2008). Additional studies indicate that cell cycle regulatory proteins are involved in neuronal death and glial cell activation after brain injury (Dyer and Cepko, 2000; Matzilevich et al., 2002).

    • Animal feed contamination by dioxins, polychlorinated biphenyls (PCBs) and brominated flame retardants

      2012, Animal Feed Contamination: Effects on Livestock and Food Safety
    • Perinatal TCDD exposure alters developmental neuroendocrine system

      2011, Food and Chemical Toxicology
      Citation Excerpt :

      It belongs to polychlorinated aromatic hydrocarbons (PAHs) group, which include polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs) and polychlorinated dibenzo-p-dioxins (PCDDs) (Koibuchi, 2006; Hennig et al., 2007; Nishijo et al., 2007; Brouillette and Quirion, 2008; Crofton, 2008; Darras, 2008; Sul et al., 2009; Tanida et al., 2009; Darnerud et al., 2010; Goodman et al., 2010; Matsumoto et al., 2010). These organohalogens are bioaccumulated and biomagnified in the food chain, meat and milk products (including breast milk) (Hassoun et al., 2000; Darnerud et al., 2010), and in the tissues of wildlife, domestic and marine animals and human’s worldwide (Gilbert, 2003; Ishida et al., 2005; Charnley and Kimbrough, 2006; Hennig et al., 2007; Brouillette and Quirion, 2008; Smith et al., 2008; Tanida et al., 2009). Particularly, TCDD is an unintentional by-product of multiple anthropogenic processes such as bleaching using chlorine gas, combustion and incineration of wastes (municipal, hospital, hazardous), fabrication of pesticides and herbicides, wood products, tobacco smoke, production of iron and steel, coal-fired electric power generation, photochemical and enzymatic reactions in sewage sludge (Viluksela et al., 2004; Hood et al., 2006; Smith et al., 2008; Tanida et al., 2009; Darnerud et al., 2010).

    • Dioxins, polychlorinated biphenyls and brominated flame retardants

      2009, Endocrine-Disrupting Chemicals in Food
    View all citing articles on Scopus
    View full text