Research report
Chronic, low-dose prenatal exposure to methylmercury impairs motor and mnemonic function in adult C57/B6 mice

https://doi.org/10.1016/j.bbr.2008.03.008Get rights and content

Abstract

Methylmercury (MeHg) has cytotoxic effects on animals and humans, and a major target organ for MeHg is the central nervous system (CNS). It is well known that the developing CNS is extremely vulnerable to MeHg-induced changes in comparison to the mature brain. Most studies have concentrated on the direct effects of high levels of prenatal MeHg exposure. Surprisingly, behavioral outcomes found in adult offspring exposed developmentally to the neurotoxic effects of chronic, low-dose mercury more akin to ingestion in humans are not well characterized. The objective of this study was to determine whether such exposure produces deleterious effects on behavior in adult mice, including motor/coordination abilities, overall activity and mnemonic function. Developing mouse fetuses were exposed in utero during gestational days 8–18 by giving pregnant C57Bl/6J female mice food containing MeHg at a daily dose of 0.01 mg/kg body weight. Adult mice prenatally exposed to MeHg exhibited significant deficits in motor abilities, coordination, and overall activity, as measured by rotarod, footprint analysis and open field. In addition, MeHg-exposed mice were impaired with respect to reference memory but not in a visible, cued version of the Morris water maze task. These results indicate that prenatal exposure to the lowest dose of MeHg examined to date can have long-lasting motor and cognitive consequences on adult offspring. These findings have far reaching implications related to putative safe levels of MeHg ingestion, particularly during pregnancy, and increasing rates of cognitive and psychological disorders (e.g. attention hyperactivity deficit disorder, autism) in our society.

Introduction

Mercury toxicity is known to be a widely recognized contributor to neural dysfunction and cognitive deficits in humans. Methylmercury (MeHg), an organic form of mercury, is one of the most toxic forms of mercury [11]. The ability of MeHg to easily cross the brain–blood barrier allows for accumulation in numerous areas of the central nervous system, including the cortex, striatum, hippocampus and cerebellum [1]. Governmental guidelines have been established to limit ingestion of mercury with the intention of reducing exposure, particularly in pregnant women [32], [34]. Due to the recycling of mercury through the environment, ingestion of small quantities of mercury due to consumption of contaminated fresh water fish and seafood remains likely [15], [20], [33], [34], [37]. For example, one study estimated as many as 500,000 babies born yearly in the U.S. have cognitive deficits that may be linked to prenatal MeHg exposure [32].

Effects of acute MeHg exposure in the human population have been extensively studied [23]. However, because the dose and duration of MeHg exposure cannot be reliably assessed in humans, little is known regarding the exposure levels at which MeHg impacts cognitive capacities, including behaviors associated with psychological disorders such as ADHD and autism, the incidence of which continue to increase at an alarming rate. In this respect, rodent models are useful as they afford precise control of MeHg exposure and assessment of mercury levels in brain in parallel with behavioral testing. Indeed, effects of chronic, moderate to high doses of postnatal MeHg exposure on juvenile and adult mice impair motor coordination and balance as well as learning and memory [3], [22], [26]. Despite a rather large focus on the acute effects of MeHg and the fact that the nervous system seems most vulnerable to MeHg exposure during prenatal development, relatively little is known regarding the effects of prenatal MeHg exposure on adult offspring, particularly at dosages that approximate human consumption. Such questions are of considerable importance given that prenatal exposure to the lowest doses of MeHg examined to date (in the range of 1 to 10+ mg/kg total exposure) can produce robust behavioral and neurobiological deficits [18], [26]. The current study was designed to test the long-term effects of low-dose prenatal MeHg exposure on male and female C57BL/6J mice that more closely approximates exposure in the human population [15], [20], [33], [34], [37]. Adult mice that were exposed to MeHg in utero were assessed for motor abilities, activity levels and spatial learning and memory. MeHg-exposed offspring demonstrated enduring deficits in each of these domains despite no detectable differences in postnatal mercury levels in brains of the adult mice exposed to MeHg prenatally compared to control mice. These results demonstrate that even very low, indirect exposure to MeHg can cause long-lasting cognitive and physical impairments in mice.

Section snippets

Animals

The adult male and female C57BL/6+/+ wild type mice used for breeding were originally purchased from The Jackson Laboratory (Bar Harbor, MA, USA) and were maintained in a breeding colony housed at the Texas A&M Laboratory Animal Resources and Research building under a constant temperature of 21–22 °C, with humidity at 45–50% and a 12 h light/dark cycle. All procedures were carried out in accordance with the regulations, policies and guidelines set forth in the Public Health Service Policy for the

Mercury (Hg) content in brain

Table 1 shows Hg content measured in the brains of pregnant adult females fed MeHg in their food as well as the brains of the prenatally exposed offspring at either embryonic day (E) 18 or 3 months of age. Hg content was significantly higher in the brains from pregnant females exposed to a total dose of 0.11 mg/kg MeHg (0.01 mg/kg/day) during gestational days E8–E18; (t(1,8) = −6.630, p < 0.05) as well as in the brains of their offspring at E18 (t(1,10) = −7.129, p < 0.05). However, prenatally exposed

Discussion

Human studies show that individuals with a diet high in MeHg-contaminated fish reliably exhibit impairment in cognitive flexibility and complex motor skills [21], [23]. More recently, Jedrychowski et al. [17] reported that relatively low, MeHg exposure through the diet of pregnant mothers was associated with cognitive and motor deficits in their children. Given this recent finding, it is becoming increasingly important to determine the parameters whereby prenatal MeHg exposure has long-term

Acknowledgements

We thank Dr. Barry Setlow, Dr. Sairam Bellum and Candi LaSarge for technical assistance. We are grateful to Nick Simon and Ian Mendez for helpful comments on this manuscript.

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