Rubber-Derived Contaminants N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine and N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone Alter Intergenerational Cholesterol Metabolism in F1 Offspring of Exposed Mice

This study examined the hepatic effects of parous exposure to the rubber-derived contaminant N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and its oxidation product, N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPDQ), in C57BL/6 mice during gestation and lactation. Both compounds exhibited dose-dependent bioaccumulation in the liver of the F0 generation and lactated F1 offspring, with 6PPDQ accumulating more due to its greater stability. Lactational transmission of both compounds was observed, and the accumulation declined with age, disappearing by 8 weeks. Notably, 6PPDQ exposure resulted in reduced body weight in mature F1 female mice, which was associated with altered cholesterol metabolism and disrupted expression of the estrogen receptor gene. In these mice, molecular analysis revealed dysregulation of key cholesterol-related genes, such as HMGCR and PCSK9. In contrast, male offspring showed less pronounced effects. These results indicate that the toxicity of 6PPD and 6PPDQ can be transmitted through placental and lactational pathways, with 6PPDQ presenting a greater risk, particularly to female mice, through its impact on cholesterol metabolism and endocrine signalling. These findings offer valuable insights for assessing the environmental and health risks associated with these compounds.