Effects of exposure to Di(2-ethylhexyl)phthalate 
during fetal period on next generation

The concept of the Developmental Origins of Health and Disease (DOHaD) is bringing new insights into the origin of lifestyle diseases: unbalanced nutrition in utero and during infancy is associated with an increased risk of lifestyle diseases. In order to clarify this association, experimental and epidemiological studies have been conducted. Maternal exposure to di(2-ethylhexyl)phthalate (DEHP), an agonist of peroxisome proliferator-activated receptor α (PPARα), decreases the number of live fetuses and newborn pups, and their body weights, and it enhances fetal desorption in wild-type mice. Similarly, these DEHP were also observed in mice expressing human PPARα, but not in PPARα-null mice. These results suggest that the DEHP toxicity in offspring is caused dependently on PPARα. DEHP suppresses the increase in the levels of plasma triglyceride (TG)/fatty acids (FAs) only in wild-type pregnant mice, suggesting that the decreased lipid levels in utero may affect the fetus development, because TG/FAs are essential in the development of fetuses. Additionally, maternal DEHP exposure decreases estrogen and progesterone balances, which may also explain the effects on fetuses and pups mentioned above. Indeed, DEHP itself or metabolite(s) may induce the toxicity, because a difference in the metabolic route is observed between the wild-type and PPARα-null mice. Thus, we were unable to conclude the causal factor(s) for the DEHP-induced offspring toxicity, that is, whether it is a direct or an indirect effect of the chemical or metabolite(s) via the toxic effects on maternal mice; however, PPARα is indeed associated with in offspring toxicity.