Does selenium modify neurobehavioural impacts of developmental methylmercury exposure in mice?

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Abstract

There is controversy as to whether low-level chronic exposure to methylmercury (MeHg) through maternal fish consumption may cause subtle effects in the developing child, owing in part to the potential ameliorating effects of beneficial seafood nutrients. The aim of the present investigation was to assess the ameliorating potential of selenium (Se; as the naturally occurring methionine complex) on the neurobehavioural toxicity of foodborne MeHg (as the naturally occurring cysteinate) in prenatally exposed mice. Pups from dams exposed to a diet containing 3 mg/kg of MeHg fed throughout gestation showed delayed fur development and impaired performance in a motor function assessment. These effects were not apparent in pups born to dams concurrently exposed to Se (at 1.3 mg/kg). These results, using natural dietary forms of the elements administered through the relevant exposure pathway, suggest only minor impacts of MeHgCys on neurobehaviour, and possible amelioration of these effects by Se.

Introduction

Fish is a valuable source of nutrition to humans, but also contains contaminants such as methylmercury (MeHg). MeHg enters the food chain as a result of the dual processes of biomethylation of mercury (Hg) in sediments of lakes and oceans, and biomagnification (Clarkson, 1997). MeHg has the ability to cross the blood–brain barrier and the placenta. Coupled with the high sensitivity of the developing foetal brain, this renders MeHg a toxicant of concern. This has been tragically demonstrated by historical episodes of accidental human poisoning from contaminated food in Minamata (Japan) and in Iraq. Perhaps the most profound finding from these incidents was the severe effects on children born to exposed mothers. The children of Minamata showed clear signs of neural damage, such as cerebral palsy, mental retardation, limb deformities and reflex disturbances (Harada, 1995). Neurodevelopmental impairment was found even in children born to mothers showing little or no signs of intoxication (Raymond and Ralston, 2004). The levels of MeHg in fish from Minamata Bay were very high, ranging from 5 to 35 mg/kg (Harada, 1995), and thus represented an extreme exposure scenario. The levels of MeHg in marine fish are normally below 0.05 mg/kg, with only a few species containing concentrations above this level (EFSA, 2004). Whether these low dose chronic exposures pose a threat to the unborn child is a question of continuing debate. A study in the Faroe Islands showed correlation between MeHg exposure and lower performance in several neuropsychological tests (Debes et al., 2006), while an investigation in the Seychelles failed to identify such a correlation (Myers et al., 2003). A possible reason for this discrepancy is the presence of several nutritional factors in fish that may modify toxicity (Clarkson and Strain, 2003).

One nutrient proposed to have an impact on MeHg toxicity is selenium (Se). For example, Se deficiency exacerbates MeHg-induced foetotoxicity and adverse effects on neurobehavioural outcomes (e.g. Watanabe et al., 1999a), while selenite supplementation decreases neurodevelopmental toxicity of MeHg in rodents (Fredriksson et al., 1993). A number of proposed mechanisms exist for explaining the ameliorating effect of Se. Se may offer protection against the oxidative damage induced by MeHg, primarily through its role as a cofactor in the important antioxidant defence enzyme glutathione peroxidise. Beyrouty and Chan (2006) proposed this mechanism to explain their data showing similar ameliorative effects of Se and the antioxidant vitamin E on MeHg toxicity in rats. An alternative mechanism, based partly on knowledge of the high affinity of Se for MeHg, is the formation of a Se–MeHg complex (Raymond and Ralston, 2004). The finding that both MeHg and Se toxicity is reduced by co-administration, supports this hypothesis (Goyer, 1997). In contrast to these studies, a recent epidemiological analysis has questioned the role of Se in ameliorating MeHg effects (Choi et al., 2008). This highlights the need for further exploration of the impact of Se on MeHg neurotoxicity.

Few studies examining the interactions between Se and MeHg have focused on dietary exposure to naturally occurring MeHg species and the organic forms of Se relevant to foodstuffs. Se in fish is predominantly found complexed to the amino acid methionine, forming seleno-methionine (SeMet; Cabanero et al., 2004). Little is known regarding the bioavailability of different chemical species of Se, but SeMet from enriched fish fillet has been shown to be more bioavailable than the commonly used form, selenite (Ørnsrud and Lorentzen, 2002). Experimentally, the use of the naturally occurring Se form is more environmentally relevant, and given the findings above, may have a more significant beneficial impact in ameliorating MeHg toxicity than inorganic Se forms.

Similarly, recent studies have shown that the form of MeHg presented through the maternal diet can significantly impact the toxicity of gestationally exposed mice pups (Lundebye et al., 2007, Glover et al., submitted for publication). Methylmercury chloride (MeHgCl), the predominant form of MeHg in laboratory studies, promoted greater neurobehavioural effects than did the form of MeHg found in fish, methylmercury–cysteine (MeHgCys; Harris et al., 2003). Differences between MeHgCl and MeHgCys bioavailability to rodents in dietary exposure (Berntssen et al., 2004), in vivo toxicity to zebrafish (Harris et al., 2003) and in vitro toxicity to cell cultures (Oyama et al., 2000) have also been shown in the literature. It is also important to dose animal models through the most relevant route of exposure—the diet. Studies utilising injection or even exposure via the drinking water may subvert important interactions between dietary constituents that may alter accumulation and toxicity.

The aim of the current experiment was to assess the ameliorating potential of dietary Se on the neurobehavioural effects of prenatal MeHg exposure in a murine model. Mice are good models for MeHg toxicity, displaying pharmacokinetic characteristics, toxic effects and dose–responses that are similar to those seen in humans (Lewandowski et al., 2003). The experimental groups received a standard dose of MeHg (as MeHgCys) and a low or high dose of supplemental Se (as seleno-L-methionine) through the diet. The effects on neurobehavioural endpoints in their offspring were determined at different stages in development and compared to control groups. The hypothesis was that supplemental Se would decrease the neurobehavioural toxicity of MeHg. To the authors’ knowledge this is the only study to date to have examined neurobehavioural outcomes in offspring born to mothers exposed to both MeHg and Se in their natural forms, through the predominant pathway of exposure—the diet.

Section snippets

Animals, housing and breeding

The experiment was approved by the National Animal Research Authority in Norway. All housing and experimental work was conducted at the National Institute of Nutrition and Seafood Research (NIFES, Norway).

A total of 64 white laboratory mice (Balb/c) were obtained from Taconic Inc., Denmark. The male mice (n = 16) were used for mating purposes, while the female mice (n = 48) were randomly divided into the experimental groups and fed different diets listed in Table 1. After an initial acclimatisation

Tissue burdens of Hg and Se

Tissue burdens of total Hg and Se in brain and liver of mice offspring are given in Fig. 2. In the absence of MeHg, there was a dose-dependent increase in Se in both liver and brain, such that at the highest Se supplementation level the tissue Se burdens were significantly higher than Control levels (p = 0.03; U-test). A similar pattern was observed for Se in the liver of offspring of mice fed diets that were also supplemented with MeHg. In the brain, Se accumulation in the presence of MeHg

Discussion

The aim of the current study was to assess the potential ameliorating effect of Se on MeHg neurobehavioural toxicity, with both elements provided in the form naturally occurring in seafood, and through the predominant route of exposure. The dose of MeHg received by mice dams in the current study (∼500 μg MeHg/kg BW/day) was significantly greater than the estimated average intake of total Hg from fish consumption by humans (0.1–1.0 μg/kg BW per week; EFSA, 2004), but elicited only relatively minor

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgements

The authors would like to thank Aase Heltveit and Berit Solli for technical expertise during mice experimentation and chemical analysis, respectively. Shalini Jayashankar is also thanked for the assistance on chemical analysis. The advice of Dr. Gillian Sales and Professor Christer Hogstrand at King's College London, and Professor Tore Syversen and Parvinder Kaur at the Norwegian University of Science and Technology is gratefully acknowledged. The study was funded by the Research Council of

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