Effects of perinatal exposure to low doses of cadmium or methylmercury on thyroid hormone metabolism in metallothionein-deficient mouse neonates

Mori, Keiichiro; Yoshida, Katsumi; Hoshikawa, Saeko; Ito, Sadayoshi; Yoshida, Minoru; Satoh, Masahiko; Watanabe, Chiho

doi:10.1016/j.tox.2006.08.017

Cited by 40 publications

(28 citation statements)

References 52 publications

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“…Some in vivo experiments have demonstrated several candidate mechanisms of perinatal exposure to MeHg, including abnormal migration of neurons and/or glias (Kakita et al 2003; Rodier et al 1984), but at higher Hg concentrations. Using exactly the same exposure protocol as the present study, we found suppressed activity of type III iodo-thyronine deiodinase, a thyroid hormone-metabolizing enzyme, in the brains of PND10 mouse neonates (Mori et al 2006), consistent with our previous study of higher MeHg doses (Watanabe et al 1999). This perturbation could be one of the candidate mechanisms responsible for the later anomalous behaviors because even a transient change in thyroid hormones during the critical period of perinatal life exerts long-term consequences (Auso et al 2004).…”

Section: Discussionsupporting

confidence: 92%

“…Several reports, however, have demonstrated protective effects of MT against MeHg toxicity, which was ascribed to the radical scavenging effect of MT (Yao et al 2000). We also showed that perinatal exposure to MeHg results in altered metabolism of thyroid hormones in neonates that was more distinct in MT-null strains than their wild-type counterparts (Mori et al 2006). The vulnerability of the MT-null strain suggests that delayed neurobehavioral toxicity due to MeHg, if it does exist, might be more distinctive in this strain.…”

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confidence: 72%

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

Yoshida

Shimizu

Suzuki

et al. 2008

Environ Health Perspect

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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.

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 72%

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

Yoshida

Shimizu

Suzuki

et al. 2008

Environ Health Perspect

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“…Factors affecting thyroid function by two other toxic metals, namely, mercury and cadmium have also been studied and mechanism involved in how they affect thyroid hormones have been proposed by [16][17][18] and by [19,20] for cadmium) but mechanism of how lead interferes in peripheral metabolism of thyroid hormones has not been proposed as described by McGregor [21] in a review article. However, as per rodent models, lead may interfere with thyroid hormone metabolism via direct reduction in thyroid hormone production from thyroid tissues [22].…”

Section: Discussionmentioning

confidence: 99%

Associations between Thyroid Hormones and Blood and Urine Lead

Jain¹

2017

Int Arch Endocrinol Clin Res

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Data from National Health and Nutrition Examination Survey for 2007-2012 were used to evaluate associations between urine and blood lead and Thyroid Stimulating Hormone (TSH), Free and Total Triiodothyronine (FT3, TT3), and Free and Total Thyroxine (FT4, TT4). Among iodine deficient as well as iodine replete males, blood lead was found to be positively associated (p <= 0.04) with TSH and urine lead was observed to have a negative association (p <= 0.01) with FT4. Among iodine deficient females, a negative association between blood lead and TT3 (p < 0.01) and a negative association between urine lead and FT3 (p = 0.01) was observed.

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“…Interestingly, MT-deficient mice display a conspicuous impairment of thyroid function upon perinatal exposure to low doses of Cd 2C , emphasizing a physiologically relevant protective role of MTs in the thyroid gland (Mori et al 2006). Furthermore, MTs exhibit cellular resistance to reactive oxygen species, e.g.…”

Section: Discussionmentioning

confidence: 99%

TSH induces metallothionein 1 in thyrocytes via Gq/11- and PKC-dependent signaling

Bäck¹,

Stöhr²,

Schäfer³

et al. 2013

Journal of Molecular Endocrinology

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Metallothioneins (MTs) are cytoprotective proteins acting as scavengers of toxic metal ions or reactive oxygen species. MTs are upregulated in follicular thyroid carcinoma and are regarded as a marker of thyroid stress in Graves' disease. However, the mechanism of MT regulation in thyrocytes is still elusive. In other cellular systems, cAMP-, calcium-, or protein kinase C (PKC)-dependent signaling cascades have been shown to induce MT expression. Of note, all of these three pathways are activated following the stimulation of the TSH receptor (TSHR). Thus, we hypothesized that TSH represents a key regulator of MT expression in thyrocytes. In fact, TSHR stimulation induced expression of MT isoform 1X (MT1X) in human follicular carcinoma cells. In these cells, Induction of MT1X expression critically relied on intact G q/11 signaling of the TSHR and was blocked by chelation of intracellular calcium and inhibition of PKC. TSHR-independent stimulation of cAMP formation by treating cells with forskolin also led to an upregulation of MT1X, which was completely dependent on PKA. However, inhibition of PKA did not affect the regulation of MT1X by TSH. As in follicular thyroid carcinoma cells, TSH also induced MT1 protein in primary human thyrocytes, which was PKC dependent as well. In summary, these findings indicate that TSH stimulation induces MT1X expression via G q/11 and PKC, whereas cAMP-PKA signaling does not play a predominant role. To date, little has been known regarding cAMP-independent effects of TSHR signaling. Our findings extend the knowledge about the PKC-mediated functions of the TSHR.

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Effects of perinatal exposure to low doses of cadmium or methylmercury on thyroid hormone metabolism in metallothionein-deficient mouse neonates

Cited by 40 publications

References 52 publications

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

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

Associations between Thyroid Hormones and Blood and Urine Lead

TSH induces metallothionein 1 in thyrocytes via Gq/11- and PKC-dependent signaling

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