Maternal exposure to di-(2-ethylhexyl) phthalate exposure deregulates blood pressure, adiposity, cholesterol metabolism and social interaction in mouse offspring
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Long-term exposure to di-(2-ethylhexyl) phthalate (DEHP) is highly associated with carcinogenicity, fetotoxicity, psychological disorders and metabolic diseases, but the detrimental effects and mechanisms are not fully understood. We investigated the effect of exposing mouse mothers to DEHP, and the underlying mechanism, on blood pressure, obesity and cholesterol metabolism as well as psychological and learning behaviors in offspring. Tail-cuff plethysmography was used for blood pressure measurement; Western blot used was for phosphorylation and expression of protein; hematoxylin and eosin staining, Nissl staining and Golgi staining were used for histological examination. The serum levels of cholesterol, triglycerides and glucose were measured by blood biochemical analysis. Hepatic cholesterol and triglyceride levels were assessed by colorimetric assay kits. Offspring behaviors were evaluated by open-field activity, elevated plus maze, social preference test and Morris water maze. Maternal DEHP exposure deregulated the phosphorylation of endothelial nitric oxide synthase and upregulated angiotensin type 1 receptor in offspring, which led to increased blood pressure. It led to obesity in offspring by increasing the size of adipocytes in white adipose tissue and number of adipocytes in brown adipose tissue. It increased the serum level of cholesterol in offspring by decreasing the hepatic capacity for cholesterol clearance. The impaired social interaction ability induced by maternal DEHP exposure might be due to abnormal neuronal development. Collectively, our findings provide new evidence that maternal exposure to DEHP has a lasting effect on the physiological functions of the vascular system, adipose tissue and nerve system in offspring.
KeywordsDi-(2-ethylhexyl) phthalate Blood pressure Adiposity Cholesterol metabolism Social interaction Offspring
The authors thank Laura Smales for help in language editing. This study was supported by grants from the National Science Council (101-2628-B-010-001-MY2, 101-2811-B-010-039, 102-2628-B-010-001-MY3 and 103-2628-B-010-040-MY3), Yen Tjing Ling Medical Foundation (CI-104-13) and Ministry of Education, Aim for the Top University Plan, Taiwan.
Conflict of interest
The authors declare no conflict of interest.
- Carbone S, Samaniego YA, Cutrera R, Reynoso R, Cardoso N, Scacchi P, Moguilevsky JA, Ponzo OJ (2012) Different effects by sex on hypothalamic-pituitary axis of prepubertal offspring rats produced by in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP). Neurotoxicology 33:78–84CrossRefPubMedGoogle Scholar
- Carbone S, Ponzo OJ, Gobetto N, Samaniego YA, Reynoso R, Scacchi P, Moguilevsky JA, Cutrera R (2013) Antiandrogenic effect of perinatal exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate increases anxiety-like behavior in male rats during sexual maturation. Horm Behav 63:692–699CrossRefPubMedGoogle Scholar
- Chiang HC, Kuo YT, Shen CC, Lin YH, Wang SL, Tsou TC (2015) Mono(2-ethylhexyl)phthalate accumulation disturbs energy metabolism of fat cells. Arch Toxicol. 28 Dec 2014. [Epub ahead of print]Google Scholar
- Ching LC, Zhao JF, Su KH, Shyue SK, Hsu CP, Lu TM, Lin SJ, Lee TS (2013) Activation of transient receptor potential vanilloid 1 decreases endothelial nitric oxide synthase phosphorylation at Thr497 by protein phosphatase 2B-dependent dephosphorylation of protein kinase C. Acta Physiol (Oxf) 209:124–135CrossRefGoogle Scholar
- Feige JN, Gelman L, Rossi D, Zoete V, Métivier R, Tudor C, Anghel SI, Grosdidier A, Lathion C, Engelborghs Y, Michielin O, Wahli W, Desvergne B (2007) The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis. J Biol Chem 282:19152–19166CrossRefPubMedGoogle Scholar
- Grande SW, Andrade AJ, Talsness CE, Grote K, Golombiewski A, Sterner-Kock A, Chahoud I (2007) A dose-response study following in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP): reproductive effects on adult female offspring rats. Toxicology 229:114–122CrossRefPubMedGoogle Scholar
- Hussain A, Nookaew I, Khoomrung S, Andersson L, Larsson I, Hulthén L, Jansson N, Jakubowicz R, Nilsson S, Sandberg AS, Nielsen J, Holmäng A (2013) A maternal diet of fatty fish reduces body fat of offspring compared with a maternal diet of beef and a post-weaning diet of fish improves insulin sensitivity and lipid profile in adult C57BL/6 male mice. Acta Physiol (Oxf) 209:220–234Google Scholar
- Lin Y, Wei J, Li Y, Chen J, Zhou Z, Song L, Wei Z, Lv Z, Chen X, Xia W, Xu S (2011b) Developmental exposure to di (2-ethylhexyl) phthalate impairs endocrine pancreas and leads to long-term adverse effects on glucose homeostasis in the rat. Am J Physiol Endocrinol Metab 301:E527–538CrossRefPubMedGoogle Scholar
- Sun X, Lin Y, Huang Q, Shi J, Qiu L, Kang M, Chen Y, Fang C, Ye T, Dong S (2014) Di (2-ethylhexyl) phthalate-induced apoptosis in rat INS-1 cells is dependent on activation of endoplasmic reticulum stress and suppression of antioxidant protection. J Cell Mol Med. doi: 10.1111/jcmm.12409 Google Scholar
- Tsuchida A, Yamauchi T, Kadowaki T (2005) Nuclear receptors as targets for drug development: molecular mechanisms for regulation of obesity and insulin resistance by peroxisome proliferator-activated receptor gamma, CREB-binding protein, and adiponectin. J Pharmacol Sci 97:164–170CrossRefPubMedGoogle Scholar
- Wang DC, Chen TJ, Lin ML, Jhong YC, Chen SC (2014) Exercise prevents the increased anxiety-like behavior in lactational di-(2-ethylhexyl) phthalate-exposed female rats in late adolescence by improving the regulation of hypothalamus-pituitary-adrenal axis. Horm Behav 66:674–684CrossRefPubMedGoogle Scholar