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Lactational Exposure of Phthalate Impairs Insulin Signaling in the Cardiac Muscle of F1 Female Albino Rats

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Abstract

Di-2-ethylhexyl phthalate (DEHP), a ubiquitous endocrine disruptor and plasticizer of polyvinyl chloride, is being used in the manufacture of consumer and medical products as well as in children’s toys. Fetuses and newborns are more sensitive to endocrine disruption. DEHP is a lipophilic substance, which could easily be transferred to the developing offspring through placenta or breast milk. DEHP alters the metabolism of the endocrine organs, which leads to energy imbalance associated with increased risk of insulin resistance, obesity and cardiovascular disease. The heart is an insulin-responsive organ. The effect of DEHP on the cardiac muscle insulin signaling remains obscure. Since the developmental period is more vulnerable to the adverse effect of DEHP, the present study was framed to study the impact of lactational exposure of DEHP on insulin signaling molecules in the cardiac muscle of F1 progeny female albino rat (postnatal day 60). Healthy dams were treated with DEHP orally (0, 1, 10 and 100 mg/kg body weight/day, respectively) from the postpartum day 1–21. Both low and high doses are relevant to the human exposure, and hence, both were used in this study. At a low dose (1 mg/kg body weight/day), obvious differences were observed in the fasting blood glucose and the insulin signaling molecule when compared to control. But marked differences were observed in the cardiac tissue insulin signaling molecules of animals treated with high doses. In conclusion, the DEHP treatment significantly increased the fasting blood glucose level and decreased the insulin receptor (IR), insulin receptor substrate (IRS-1), p-IRS-1Tyr632, p-AktSer473, plasma membrane glucose transporter (GLUT4), 14C-2-deoxyglucose uptake and the 14C-glucose oxidation. Conversely, Akt and GLUT4 protein in cytosol remained unaltered compared to control. Lactational exposure of DEHP impairs insulin signal transduction and glucose oxidation in the cardiac muscle of the F1 female albino rats, suggesting its possible role in the development of type 2 diabetes.

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Abbreviations

ATP:

Adenosine triphosphate

Atf-4:

Activating transcription factor 4

Atf-6:

Activating transcription factor 6

Bip:

Binding immunoglobulin protein

CPM:

Counts per minute

FSH:

Follicle-stimulating hormone

GLUT4:

Glucose transporter 4

IR:

Insulin receptor

IRS-1:

Insulin receptor substrate 1

IU:

International units

JNK:

C-Jun N-terminal kinase

MEHP:

Mono-(-2-ethylhexyl phthalate)

MEHHP:

Mono-(2-ethyl-5-hydroxyhexyl) phthalate

MEOHP:

Mono-(2-ethyl-5-oxohexyl) phthalate

mM:

Millimolar

nM:

Nanomolar

OECD:

Organization for economic cooperation and development

Pdx1:

Pancreatic duodenal homeobox-1

PPARγ:

Peroxisome proliferator-activated receptor γ

PPARα:

Peroxisome proliferator-activated receptor α

Ucp2:

Uncoupling protein-2

μCi:

Microcurie

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Acknowledgments

Financial assistance from UGC-SAP-DRS, UGC-ASIST and DST-FIST programs are gratefully acknowledged.

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  1. Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India

    Viswanathan Mangala Priya, Chinnaiyan Mayilvanan, Narasimhan Akilavalli, Parsanathan Rajesh & Karundevi Balasubramanian

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Correspondence to Karundevi Balasubramanian.

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Mangala Priya, V., Mayilvanan, C., Akilavalli, N. et al. Lactational Exposure of Phthalate Impairs Insulin Signaling in the Cardiac Muscle of F1 Female Albino Rats. Cardiovasc Toxicol 14, 10–20 (2014). https://doi.org/10.1007/s12012-013-9233-z

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