Mechanisms of arsenic toxicity in the nematodes Caenorhabditis elegans

Arsenic (As) permeates the environment. As a result, humans are continually exposed to it. This study investigates the toxicity regulation of arsenic in Caenorhabditis elegans. The specific aims of the research in this study are: (1) to determine whether or not arsenic exerts neurotoxic effects and what factors and mechanisms are involved; (2) to determine whether or not arsenic accelerates aging process and what factors and mechanisms are involve; and (3) to determine whether or not arsenic exerts transgenerational reproductive toxicity and what factors and mechanisms are involved. For specific aim 1, we investigated the possible roles of oxidative stress in arsenite (As(III))-induced neurotoxicity in C. elegans The results showed that exposure to As(III) (100μM) caused a decrease in locomotor behaviors (frequencies of body bends, head thrashes, and reversals) of C. elegans. In addition, As (III) (100 μM) exposure decreased thermotactic behaviors, and induced severe deficits in the structural properties of the amphid finger neuron (AFD). Exposure to As(III) (100 μM) also caused an elevated production of reactive oxygen species (ROS). Pretreatment with the antioxidant curcumin (100 µM) ameliorated the decrease in locomotor and thermotactic behavior, and the formation of deficits in the structural properties of AFD sensory neurons in As(III)-exposed nematodes. Our study suggests that oxidative stress plays a crucial role in the As(III)-induced neurotoxic effects on locomotor behavior and the structures and function of AFD sensory neurons in As(III)-exposed nematodes. For specific aim 2, we investigated the effects and the underlying mechanisms of chronic arsenite exposure on the aging process in C. elegans. The results showed that prolonged arsenite (100, 500, and 1000 μM) exposure caused significantly decreased lifespan compared to non-exposed ones. In addition, arsenite exposure (100 μM) caused significant changes of age-dependent biomarkers, including a decrease of defecation frequency, accumulations of intestinal lipofuscin and lipid peroxidation in age-dependent manner in C. elegans. Further evidence revealed that intracellular reactive oxygen species (ROS) level was significantly increased in age-dependent manner upon arsenite exposure (100 μM). Moreover, the mRNA levels of transcriptional makers of aging (hsp-16.1, hsp-16.49, and hsp-70) were increased in aged worms under arsenite exposure (100 μM). Finally, we showed that daf-16 mutant worms were more sensitive to arsenite exposure on lifespan and failed to induce the expression of its target gene sod-3 in aged daf-16 mutant under arsenite exposure (100 μM). Our study demonstrated that chronic arsenite exposure resulted in accelerated aging in C. elegans. The overproduction of intracellular ROS and the transcription factor DAF-16/FOXO play key roles in mediating the accelerated aging process by arsenite exposure in C. elegans. This study implicates a potential exoctoxicological and health risk of arsenic in the environment. For specific aim 3, the transgenerational reproduction defects of arsenite on C. elegans were investigated by examining the parental generation (F0) to the fourth offspring generation (F4). The results showed that the total brood size of the C. elegans was significantly reduced (33%) in the F0 by arsenite exposure (1 mM), and the reduction of the brood size was also observed in the offspring generations (F1 to F4), after the arsenite exposure was removed. In addition, both adult worms from F0 and F1 generation accumulated arsenite and arsenate when L4 larvae of F0 were exposed to 1mM arsenite for 24h. Moreover, the mRNA level of the H3K4me2 demethylase LSD/KDM1, spr-5, was significantly reduced in F0 by arsenic exposure (1 mM). Likewise, the mRNA level of spr-5 was also significantly reduced in F1 to F3 generations. In addition, di-methylation of global H3K4 was increased in F0 to F3 generations. Our study suggests that prenatal arsenic exposure causes transgenerational reproduction defects in C. elegans which might be attributed to epigenetic change via Histone H3K4 di-methylation.