Developmental Methylmercury Exposure Induced and Age-Dependent Glutamatergic Neurotoxicity in Caenorhabditis elegans

Abstract

Developmental methylmercury (MeHg) exposures cause latent neurotoxic effects in adults; however, the mechanisms underlying the latent neurotoxicity are not fully understood. In the current study, we used C. elegans as an animal model to investigate the latent neurotoxic effects of developmental MeHg exposures on glutamatergic neurons. The young larvae stage 1 worms were exposed to MeHg (0.05 ~ 5 µM) for 48 h. The morphological and behavioral endpoints of glutamatergic neurons were compared when worms reached to adult stages including the young adult stage (day 1 adult) and the old adult stage (day 10 adult). Here, we showed that C. elegans glutamatergic neurons were morphologically intact following low or medium MeHg exposures (0.05 ~ 0.5 µM). The morphological damage of glutamatergic neurons appeared to be pronounced in day 10 adults developmentally exposed to 5 µM MeHg. Behavioral assays also showed an age-dependent latent effect of MeHg. In the nose touch response assay, only day 10 adult worms exhibited a functional decline following prior 5 µM MeHg exposure. Moreover, the disruption of NaCl memory appeared only in day 1 adults following MeHg exposures but not in day 10 adults. The expression of C. elegans homologs of mammalian vesicular glutamate transporter (eat-4) was repressed in day 1 adults, while the glutamate receptor homolog (glr-1) was upregulated in day 10 adults with 5 µM MeHg. In the comparison of age-dependent changes in the insulin-like pathway (daf-2/age-1/daf-16) following MeHg exposures, we showed that the daf-2/age-1/daf-16 pathway was mobilized in day 1 adults but repressed in day 10 adults. Collectively, our data supports a conclusion that MeHg-induced glutamatergic neurotoxicity exhibits an age-dependent pattern, possibly related to the prominent changes in age-dependent modulation in the glutamatergic neurotransmission and metabolic pathways.

Keywords: Caenorhabditis elegans; Glutamate receptor; Glutamatergic neuron; Methylmercury; Vesicular glutamate transporter.