Emergence of Delayed Methylmercury Toxicity after Perinatal Exposure in Metallothionein-Null and Wild-Type C57BL Mice

Abstract

BackgroundAlthough a long latency period of toxicity after exposure to methylmercury (MeHg) is known to exist in humans, few animal studies have addressed this issue. Substantiation of delayed MeHg toxicity in animals would affect the risk evaluation of MeHg.ObjectivesOur goal in this study was to demonstrate the existence of a latency period in a rodent model in which the toxicity of perinatal MeHg exposure becomes apparent only later in life. Our study included metallothionein (MT) knockout mice because studies have suggested the potential susceptibility of this strain to the neurodevelopmental toxicity of MeHg.MethodsPregnant MT-null and wild-type C57Bl/6J mice were exposed to MeHg through their diet containing 5 μg Hg/g during gestation and early lactation. We examined behavioral functions of the offspring using frequently used paradigms, including open field behavior (OPF), passive avoidance (PA), and the Morris water maze (MM), at ages of 12–13 and 52–53 weeks.ResultsAt 12 weeks of age, behavioral effects of MeHg were not detected, except for OPF performance in MeHg-exposed MT-null females. At 52 weeks of age, the MeHg-exposed groups showed poorer performance both in PA and MM, and their OPF activity differed from controls. These effects of MeHg appeared exaggerated in the MT-null strain. The brain Hg concentration had leveled off by 13 weeks of age.ConclusionsThe results suggest the existence of a long latency period after perinatal exposure to low-level MeHg, in which the behavioral effects emerged long after the leveling-off of brain Hg levels. Hence, the initial toxicologic event responsible for the late effects should have occurred before this leveling-off of brain Hg.

Emergence of delayed behavioral effects in offspring mice exposed to low levels of mercury vapor during the lactation period

“…We cannot explain how the emergence of delayed neurobehavioral effects resulted from postnatal exposure to Hg 0 at present. In the present study, as described in previous paper (Yoshida et al, 2008), physiological events with acceleration of the aging process may contribute to the delayed Hg 0 toxicity due to postnatal exposure. However, age-related behavioral changes need to be clarified in further experiments.…”

“…On the other hand, the emergence of behavioral effects that accompany the aging process after exposure of offspring to low-level Hg 0 has not been studied in detail. However, results revealed that although the behavioral effects are slight, exposure to Hg 0 during developing periods resulted in the emergence of delayed Hg 0 toxicity in older mice, as well as the emergence of delayed methylmercury toxicity after perinatal exposure (Yoshida et al, 2008). The central nervous system is known to be susceptible to mercury and that exposure to Hg 0 causes more severe damage to offspring than adults.…”

“…Few animal studies have addressed the latency period of toxicity after exposure to mercury. Recently, Yoshida et al (2008) reported the existence of a long latency period in MT-I/II null mice after perinatal exposure to low-level methylmercury, in which the behavioral effects emerged long after the leveling-off of brain mercury levels. On the other hand, the emergence of behavioral effects that accompany the aging process after exposure of offspring to low-level Hg 0 has not been studied in detail.…”

Hormetic effect of methylmercury on Caenorhabditis elegans

“…C. elegans express nearly 50 GSTs (van Rossum et al , 2001), approximately 10 HSPs of the HSP70 family (Heschl and Baillie, 1989), and 2 MTs (Freedman et al , 1993). Our results indicate that some of the same mechanisms are involved in detoxification in C. elegans as have been identified in other model systems (Sacco et al , 1997; Schlawicke Engstrom et al , 2008; Yoshida et al , 2008). …”

“…Due to their high cysteine content, MTs have a strong affinity for MeHg. Additionally, MeHg has been shown to induce MT expression (Rising et al , 1995; Tsui and Wang, 2005) and alterations in behavior of MT-null animals (Yoshida et al , 2008). Although GSH, HSP, and MT have been implicated in resistance to MeHg toxicity, researchers have yet to elucidate their precise roles in detoxification.…”