Multiorgan toxicity of 3-Chloromethcathinone (3-CMC) in male and female mice: translational implications for liver, kidney, and spleen.

Growing evidences reporting increasing diffusion and toxic effects of synthetic cathinones (SCs) within the recreational market of novel psychoactive substance (NPS) upstretched public health concerns. However, However, the pathophysiological responses underlying their toxicity remain poorly understood. In particular, despite its increasing circulation, data regarding 3-Chloromethcathinone (3-CMC) toxicological profile and pharmacological properties remains limited. To fill this gap, this in vivo study explored systemic effects of 3- CMC repeated exposures in mice, comparing sex differences. Male and female mice received i.p. injections of 3-CMC once weekly for five consecutive weeks (total of 35 days), with doses escalating from 0.1 to 1, 6, 10 and 30mg·kg⁻¹ in successive weeks (vehicle: 0.004ml·g⁻¹, i.p.), for a total of five injections (D1, D2, D3, D4 and D5) with a 6-day period of washout between each consecutive injection, and were then assigned to blood/tissue analyses. Blood and urine biochemical parameters were measured, paralleled by histopathological and immunohistochemical analyses on different target organs, i.e. liver, kidney and spleen. Our data demonstrated significant alterations in blood and urine biochemical parameters, accompanied by histopathological changes in all evaluated tissues, both in male and female animals, paralleled by enhanced cell death pathways activation. From a translational perspective, these preclinical findings provide crucial evidences concerning 3-CMC systemic toxicity, developing knowledge on potential health risks posed by this NPS. These data may also lead the way for further researches on CMC compounds and related toxidromes, aiding development of effective clinical strategies helping physicians in patients' management after exposure to SCs.