Multi- and trans-generational effects of di-n-octyl phthalate on behavior, lifespan and reproduction of Caenorhabditis elegans through neural regulation and lipid metabolism

Di-n-octyl phthalate (DOP) is one important phthalate analog whose toxicities need comprehensive investigation to fully demonstrate phthalates health risks. In the present study, apical effects of DOP on behavior, lifespan and reproduction and the underlying mechanisms were explored in Caenorhabditis elegans for four consecutive generations (F1 to F4) and the trans-generational effects were also measured in the great-grand-children (T4 and T4') of F1 and F4. Multi-generational results showed that DOP caused both stimulation and inhibition on head swing, body bending, reverse, Omega steering, pharyngeal pump and satiety quiescence. The stimulation and inhibition altered over concentrations and across generations, and the alteration was the greatest in reverse locomotion which showed both concentration-dependent hormesis and trans-hormesis. DOP stimulated lifespan and inhibited reproduction, showing trade-off relationships. Significant trans-generational residual effects were found in T4 and T4' where the exposure was completed eliminated. Moreover, both similar and different effects were found in comparisons between F1 and F4, between F1 and T4, between F4 and T4' and also between T4 and T4'. Further analysis showed close connections between effects of DOP on neurotransmitters (including dopamine, acetylcholine, γ-aminobutyric acid and serotonin) and enzymes in lipid metabolism (including lipase, acetyl CoA carboxylase, fatty acid synthetase, carnitine palmitoyl-transferase, glycerol phosphate acyltransferase and acetyl CoA synthetase). Moreover, the close connections were also found between biochemical and apical effects. Notably, the connections were different in multi- and trans-generational effects, which urged further studies to reveal the response strategies underlying the exposure scenarios.