Dimethyl phthalate induces blood immunotoxicity through oxidative damage and caspase-dependent apoptosis

Dimethyl phthalate (DMP), a low-molecular-weight phthalate ester, exists in ectoparasiticides, plastics, and insect repellants, and has been linked to neurotoxic, reproductive, and endocrine disruptive responses. However, its blood immunotoxic effects and mechanism are still poorly understood. In this study, rats were exposed to gradient concentrations of DMP through intragastric administration to assess the blood immunotoxic effects in the combined assay of biomarker, cytometry, and transcriptomics. DMP treatment altered the redox status of rats, thus causing oxidative damage. Significantly decreased blood cell counts and disordered antibody and cytokine secretion were observed in treated rats, suggesting the suppressed immune defense and destructed inflammatory regulation. Flow cytometry showed that in lymphocytes, especially CD3⁺CD4⁺ T cells, the occurrence of apoptosis/necrosis was positively related to DMP exposure level. Transcriptomics revealed an oxidative stress-related mechanism. The overexpression of the Bcl-2 family genes and the activation of the Fas/FasL pathway triggered downstream caspase cascade and caused reactive oxygen species signaling-mediated apoptosis/necrosis. To the best of our knowledge, it was the first report that the exposure to low-molecular-weight phthalate esters potentially triggered blood immunotoxicity. The result and underlying mechanisms can provide an essential basis for understanding phthalate ester toxicity and usage regulation.