Nicotinamide mononucleotide rescues perinatal arsenic-induced autism-like behaviours via modulation of NAD+ metabolism in mice.

Recent epidemiological studies have indicated that exposure to arsenic (As), particularly during key phases of central nervous system development, may be an environmental risk factor for autism spectrum disorder (ASD). While nicotinamide mononucleotide (NMN) confers neuroprotection by elevating tissue nicotinamide adenine dinucleotide (NAD+), its efficacy against ASD pathophysiology remains unexplored. Here, a mouse model of perinatal As exposure (1.2 mg/kg/d) and NMN intervention (500 mg/L) was employed, and NMN was found to rescue As-induced NAD+ depletion in offspring brain tissues. This restoration coincided with increased synaptic density in the cortex and significant attenuation of autism-like behavioural phenotypes. Additionally, NMN restored As-induced intestinal dysbiosis and enriched beneficial genera including Lactobacillus and Akkermansia, restoring the Firmicutes/Bacteroidetes ratio. Consistently, As exposure exacerbated inflammatory damage in colonic tissues, elevated pro-inflammatory cytokine levels in serum, and activated cortical microglia and astrocytes. In contrast, NMN supplementation markedly alleviated these inflammatory and neuroimmune disturbances. Notably, NMN also increased Clostridium species, which synthesise vitamin B3 (VB3), a precursor of NAD+ . Moreover, the intervention alleviated the As-induced disruption of colonic epithelial tight junctions and polarity, while concomitantly upregulating NAD+ synthase and NAD+ precursor transporter proteins that were inhibited by As. Collectively, these actions restored perinatal As-induced NAD+ deficits in offspring, providing novel mechanistic insights into the therapeutic potential of NMN against As-driven autism-like phenotypes. These findings offer a foundation for dietary supplementation with NMN as a strategy for clinical translation.