Maternal Di-(2-ethylhexyl)-phthalate Exposure Influences Essential Fatty Acid Homeostasis in Rat Placenta

Abstract

Maintaining essential fatty acid (EFA) homeostasis during pregnancy is critical for fetal development. As the organ that controls the maternal-to-fetal supply of nutrients, the placenta plays a significant role in guiding EFA transfer to the fetus. Many EFA homeostasis proteins are regulated by peroxisome proliferator-activated receptors (PPARs). The metabolites of di-(2-ethylhexyl)-phthalate (DEHP), a ubiquitous environmental contaminant, might influence EFA homeostasis via trans-activation of PPARs with subsequent downstream effects on EFA transporters and enzymes. To investigate DEHP's effect on placental/fetal EFA homeostasis, female Sprague-Dawley rats were orally gavaged with either vehicle or DEHP at 750 or 1500 mg/kg/day from gestational day (GD) 0 to GD 19. Changes in the expression of several EFA homeostasis regulating proteins were determined in the junctional (JXN) and labyrinthine (LAB) zones of the placenta, including PPAR isoforms (α, β and γ), fatty acid translocase (FAT/CD36), fatty acid transport protein 1 (FATP1), plasma membrane fatty acid binding protein (FABPpm), heart cytoplasmic fatty acid binding protein (HFABP), cytochrome P450 (CYP) 4A1, and cyclooxygenase (COX)-1 and -2. Additionally, effects of DEHP maternal exposure on the placental transfer and fetal distribution of representative EFAs, arachidonic acid (AA) and docosahexaenoic acid (DHA), and the placental production of prostaglandins (PGs) were investigated. Expression of PPARα, PPARγ, FAT/CD36, FATP1, HFABP and CYP4A1 was up-regulated in JXN and/or LAB while COX-2 was down-regulated in JXN. PPARβ, FABPpm, and COX-1 demonstrated variable expression. Reduced directional maternal-to-fetal placental transfer and altered fetal distribution of AA and DHA were observed in concordance with a decreased total placental PG production. These results correlate with previous in vitro data, suggesting that DEHP could influence placental EFA homeostasis with potential downstream effects in the developing fetus.

Antenatal Glucocorticoid Therapy Accelerates ATP Production With Creatine Kinase Increase in the Growth-Enhanced Fetal Rat Heart

“…23 In the present study, the PPARγ level in nuclei was significantly increased in the DEX groups of 21-day fetuses (137.92±56.29%) and 1-dayold neonates (59.28±24.201%) compared with the respective controls (21-day: 38.47±15.70%; 1-day-old: 100.00±40.82%). Antenatal DEX administration resulted in an approximately 3.6-fold increase in PPARγ in 21-day fetuses ( Figure 7A).…”

“…PPARs are involved in energy metabolism and mitochondrial function-related genes, including CK, during cardiac development, 23,42 although PPARγ mainly contributes to lipid metabolism in cardiomyocytes. 42 Interestingly, we found that the expression of PPARα remained low in the 21-day fetal heart, but antenatal DEX administration significantly increased PPARγ levels in the nuclei of 21-day fetal hearts.…”

Combined arsenic and di-(2-ethylhexyl) phthalate exposure elicits responses in brain ATPases different from hepatic and renal activities in rats

“…ATPase is known to be sensitive to its lipid milieu, and both arsenic and DEHP have been reported to perturb lipid metabolism (Bhattacharjee and Pal, 2014;Muthumani and Milton, 2013;Jia et al, 2015;Xu et al, 2009). The changes in lipid contents caused by these agents may thus, explain the alterations in the enzyme activity.…”

The Epigenetic Lorax: Gene–Environment Interactions in Human Health

“…Exposure is through inhalation at the workplace, oral ingestion or injection during medical procedures. DEHP is an antiandrogen and can lead to reproductive effects (follicular atresia, inhibition of follicle-stimulating hormone activity, pre eclampsia, miscarriage, reduced estrogen, prolonged estrus and premature thelarche in various species [39,44,102,104,109,115–123]) and other effects in various species [44,90,116,124–127]. No detailed data exist on epigenetic effects of phthalates, but effects on imprinting have been reported.…”

“…EDCs may exert indirect, long-term effects on progeny health via effects on the placenta. The placenta is a target of EDCs [44,116,126,148–153], and may be especially sensitive [153,154]. Placental function can be altered by epigenetic changes, such as loss of imprinting [155–160].…”