Methylmercury interferes with glucocorticoid receptor: Potential role in the mediation of developmental neurotoxicity.

Methylmercury (MeHg) is a widespread environmental contaminant with established developmental neurotoxic effects. Computational models have identified glucocorticoid receptor (GR) signaling to be a key mediator behind the birth defects induced by Hg, but the mechanisms were not elucidated. Using molecular dynamics simulations, we found that MeHg can bind to the GR protein at Cys736 (located close to the ligand binding site) and distort the conformation of the ligand binging site. To assess the functional consequences of MeHg interaction with GR, we used a human cell line expressing a luciferase reporter system (HeLa AZ-GR). We found that 100 nM MeHg does not have any significant effect on GR activity alone, but the transactivation of gene expression by GR upon Dex (a synthetic GR agonist) administration was reduced in cells pre-treated with MeHg. Similar effects were found in transgenic zebrafish larvae expressing a GR reporter system (SR4G). Next we asked whether the effects of developmental exposure to MeHg are mediated by the effects on GR. Using a mutant zebrafish line carrying a loss-of-function mutation in the GR (grS357) we could show that the effects of developmental exposure to 2.5 nM MeHg are mitigated in absence of functional GR signaling. Taken together, our data indicate that inhibition of GR signaling may have a role in the developmental neurotoxic effects of MeHg.

Influence of dopamine on flash visual evoked potentials (FVEP) in prenatally mercury intoxicated rats.

The female adult white Wistar rats were given tap water (control) or 50 ppm of methylmercury chloride (MMC) ad libitum throughout their pregnancies. Newborn rats drank mother's milk during the first 21 days after delivery and then only tap water. The study was carried out on three-month old offsprings of white Wistar rats. The flash visual evoked potentials (FVEP) were recorded before and after injecting of 10 microl 0.9% saline, 50 or 100 nmols of dopamine (DA) into the lateral brain ventricle by method used before in our laboratory. The amplitude of the first deep negative (N(1)) peak significantly increased to 109-114% after both doses of DA in the control group and to 138-139% in mercury-treated animals. The amplitude of the next positive (P(1)) wave decreased to 94% and 86% in the control group after 50 and 100 nmols of DA, respectively. In Hg-treated group after 50 nmols of DA, the value dropped down to 91%, but increased to 109% after 100 nmols of DA. The increasing of DeltaN(1)P(1) was observed in the control group to 112% after 50 nmols and to 109% after 100 nmols of DA and in Hg-exposed rats, respectively, to 127% and to 129%. The described changes were statistically significant (p < 0.05). The N(1) and P(1) latencies were prolonged in the control group after both doses of DA. In Hg-treated group, the prolongation of N(1) latency was recorded, while the P(1) latency was not changed. We concluded that prenatal Hg intoxication disturbed the effect of DA on FVEP.

Developmental neuropathology of environmental agents.

The developing central nervous system (CNS) is more vulnerable to injury than the adult one. Although a great deal of research has been devoted to subtle effects of developmental exposure, such as neurobehavioral changes, this review instead focuses on a number of chemicals that have been shown, in several experimental models as well as humans, to cause morphological changes in the developing nervous system. Chemicals that are discussed include methylmercury (MeHg), lead (Pb), antiepileptic drugs, and ethanol. Additionally, the issue of silent neurotoxicity, i.e., persistent morphological and/or biochemical injury that remains clinically unapparent until later in life, is discussed.