Abstract
Phthalates (such as DEHP) and bisphenol A (BPA) are widely used chemicals in plastics manufacturing and exert public health concerns as endocrine disrupters. This study was designed to investigate the deleterious effect of DEHP and BPA on endocrine profile of pregnant female rats and the combined treatment with ginseng extract (Panax ginseng). Seventy-two pregnant rats were divided into six groups (control, ginseng, DEHP, BPA, Gin + DEHP, and Gin + BPA), 12 females per each group. The drugs were supplemented from pregnancy day 0 until day 20. Determination of serum sex hormones (testosterone, progesterone, and estradiol) were determined on days 4, 10, and 20 of pregnancy. mRNA transcripts of STAR, HSD17B3, CYP17, AKT1, and PTEN were relatively quantified against ACTB in the ovary and placenta of days 10 and 20 pregnant females by relative quantitative polymerase-chain reaction (RQ-PCR). DEHP and BPA significantly decreased the endocrine profile of testosterone, progesterone, and estradiol of days 10 and 20 of pregnant females. Combined administration of these chemicals along with ginseng extracts has returned the hormones to normal levels when compared with the control group. The ovarian and placental CYP17 and HSD17B3 mRNA transcripts showed variable expression pattern in both tissues and they were significantly affected by DEHP and BPA administration, concomitantly correlating to STAR, AKT1, PTEN, progesterone, and testosterone levels on pregnancy days 10 and 20. The results confirm the reprotoxicity of DEHP and BPA as endocrine disruptors and indicate that ginseng could be used to alleviate the toxic effects of these chemicals.
Similar content being viewed by others
Abbreviations
- AKT1:
-
Alpha serine/threonine-protein kinase
- BPA:
-
4,4′-Isopropylidenediphenol or bisphenol A
- CYP17:
-
Cytochrome P450 17alpha hydroxylase/17,20 lyase
- DEHP:
-
Bis(2-ethylhexyl) benzene-1,2-dicarboxylate or bis(2-ethylhexyl) phthalate
- Gin:
-
Ginseng
- HSD17B3:
-
17β-Hydroxysteroid dehydrogenase 3
- PTEN:
-
Phosphatase and tensin homolog
- STAR:
-
Steroidogenic acute regulatory protein
References
Attele AS, Wu JA, Yuan CS (1999) Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 58:1685–1693
Barlow NJ (2003) Quantitative changes in gene expression in fetal rat testes following exposure to Di(n-butyl) phthalate. Toxicol Sci 73:431–441
Brotons JA, Olea-Serrano MF, Villalobos M, Pedraza V, Olea N (1995) Xenoestrogens released from lacquer coatings in food cans. Environ Health Perspect 103:608–612
Cheng H-X, Sun A-H, Wang Y-G, Gao Y, Jiang Y (2016) Evaluation of regulation of Salvia miltiorrhiza and Panax ginseng on rat liver CYP450 using multiple reaction monitoring. Chin Tradit Herb Drug 47:3647–3655
Choi J, Kim T-H, Choi T-Y, Lee MS (2013) Ginseng for health care: a systematic review of randomized controlled trials in Korean literature. PLoS One 8:e59978
Christiansen S, Boberg J, Axelstad M, Dalgaard M, Vinggaard AM, Metzdorff SB, Hass U (2010) Low-dose perinatal exposure to di (2-ethylhexyl) phthalate induces anti androgenic effects in male rats. Reprod Toxicol 30:261–270
DeVore NM, Scott EE (2012) Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001. Nature 482:116–119
Diamanti-Kandarakis E, Bourguignon J-P, Giudice LC, Hauser R, Prins GS, Soto AM, Zoeller RT, Gore AC (2009) Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev 30:293–342
Durkee TJ, McLean MP, Hales DB, Payne AH, Waterman MR, Khan I, Gibori G (1992) P450(17 alpha) and P450SCC gene expression and regulation in the rat placenta. Endocrinology 130:1309–1317
El-Drieny EA, Soliman GM, Bayomy NA (2009) Histological study of the effect of di (2-ethylhexyl) phthalate (DEHP) on the adrenal cortex of adult male albino rat and the possible protective role of ginseng. Egypt J Histol 32:109–117
Feng Y, Zhang P, Zhang Z, Shi J, Jiao Z, Shao B (2016) Endocrine disrupting effects of triclosan on the placenta in pregnant rats. PLoS One 11:e0154758
Fenichel P, Chevalier N, Brucker-Davis F (2013) Bisphenol A: an endocrine and metabolic disruptor. Ann Endocrinol (Paris) 74:211–220
Froment P, Bontoux M, Pisselet C, Monget P, Dupont J (2005) PTEN expression in ovine granulosa cells increases during terminal follicular growth. FEBS Lett 579:2376–2382
Fukuda S, Orisaka M, Tajima K, Hattori K, Kotsuji F (2009) Luteinizing hormone-induced Akt phosphorylation and androgen production are modulated by MAP kinase in bovine theca cells. J Ovarian Res 2:17
Gillis CN (1997) Panax ginseng pharmacology: a nitric oxide link? Biochem Pharmacol 54:1–8
Gray LE (2006) Chronic di-n-butyl phthalate exposure in rats reduces fertility and alters ovarian function during pregnancy in female Long Evans hooded rats. Toxicol Sci 93:189–195
Gibori G, Sridaran R (1981) Sites of androgen and estradiol production in the second half of pregnancy in the rat. Biol Reprod 24:249–256
Guo M, Lai L, Zong T, Lin Y, Yang B, Zhang L, Li M, Kuang H (2015) Exposure to di(2-ethylhexyl) phthalate inhibits luteal function via dysregulation of CD31 and prostaglandin F2alpha in pregnant mice. Reprod Biol Endocrinol 13:11
Han SY, Kim J, Kim E, Kim SH, Seo DB, Kim J-H, Shin SS, Cho JY (2017) AKT-targeted anti-inflammatory activity of Panax ginseng calyx ethanolic extract. J Ginseng Res. https://doi.org/10.1016/j.jgr.2017.06.003
Hannon PR, Flaws JA (2015) The effects of phthalates on the ovary. Front Endocrinol 6:8
Hannon PR, Brannick KE, Wang W, Flaws JA (2015) Mono(2-ethylhexyl) phthalate accelerates early folliculogenesis and inhibits steroidogenesis in cultured mouse whole ovaries and antral follicles. Biol Reprod 92:120
Jackson JA, Albrecht ED (1985) The development of placental androstenedione and testosterone production and their utilization by the ovary for aromatization to estrogen during rat pregnancy. Biol Reprod 33:451–457
Jin G, Ma J (2017) Protective effect of ginsenoside Rg1 on isoproterenol-induced acute myocardial ischemia in rats. Int J Clin Exp Med 10:4100–4106
Kallen CB, Billheimer JT, Summers SA, Stayrook SE, Lewis M, Strauss JF (1998) Steroidogenic acute regulatory protein (StAR) is a sterol transfer protein. J Biol Chem 273:26285–26288
Koch HM, Preuss R, Angerer J (2006) Di(2-ethylhexyl)phthalate (DEHP): human metabolism and internal exposure—an update and latest results1. Int J Androl 29:155–165
Konieczna A, Rutkowska A, Rachon D (2015) Health risk of exposure to bisphenol A (BPA). Rocz Panstw Zakl Hig 66:5–11
Kopalli SR, Hwang SY, Won YJ, Kim SW, Cha KM, Han CK, Hong JY, Kim SK (2015) Korean red ginseng extract rejuvenates testicular ineffectiveness and sperm maturation process in aged rats by regulating redox proteins and oxidative defense mechanisms. Exp Gerontol 69:94–102
Lai M-S, Cheng Y-S, Chen P-R, Tsai S-J, Huang B-M (2014) Fibroblast growth factor 9 activates Akt and MAPK pathways to stimulate steroidogenesis in mouse Leydig cells. PLoS One 9:e90243
Larsson K, Ljung Björklund K, Palm B, Wennberg M, Kaj L, Lindh CH, Jönsson BAG, Berglund M (2014) Exposure determinants of phthalates, parabens, bisphenol A and triclosan in Swedish mothers and their children. Environ Int 73:323–333
Lee CS, Bae IH, Han J, Choi GY, Hwang KH, Kim DH, Yeom MH, Park YH, Park M (2014) Compound K inhibits MMP-1 expression through suppression of c-Src-dependent ERK activation in TNF-alpha-stimulated dermal fibroblast. Exp Dermatol 23:819–824
Li H, Liu SY, Wang B (2014) Progress of the regulation effect of ginsenosides on HPA axis. Yao Xue Xue Bao 49:569–575. (in Chinese)
Liu T, Li N, Zhu J, Yu G, Guo K, Zhou L, Zheng D, Qu X, Huang J, Chen X, Wang S, Ye L (2014) Effects of di-(2-ethylhexyl) phthalate on the hypothalamus-pituitary-ovarian axis in adult female rats. Reprod Toxicol 46:141–147
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25:402–408
Makker A, Goel MM, Mahdi AA (2014) PI3K/PTEN/Akt and TSC/mTOR signaling pathways, ovarian dysfunction, and infertility: an update. J Mol Endocrinol 53:R103–R118
Mani AM, Fenwick MA, Cheng Z, Sharma MK, Singh D, Wathes DC (2009) IGF1 induces up-regulation of steroidogenic and apoptotic regulatory genes via activation of phosphatidylinositol-dependent kinase/AKT in bovine granulosa cells. Reproduction 139:139–151
Matt DW, MacDonald GJ (1984) In vitro progesterone and testosterone production by the rat placenta during pregnancy. Endocrinology 115:741–747
Muhlhauser A, Susiarjo M, Rubio C, Griswold J, Gorence G, Hassold T, Hunt PA (2009) Bisphenol A effects on the growing mouse oocyte are influenced by diet. Biol Reprod 80:1066–1071
Nteeba J, Sanz-Fernandez MV, Rhoads RP, Baumgard LH, Ross JW, Keating AF (2015) Heat stress alters ovarian insulin-mediated phosphatidylinositol-3 kinase and steroidogenic signaling in gilt ovaries. Biol Reprod 92(148):148
Peretz J, Vrooman L, Ricke WA, Hunt PA, Ehrlich S, Hauser R, Padmanabhan V, Taylor HS, Swan SH, VandeVoort CA, Flaws JA (2014) Bisphenol A and reproductive health: update of experimental and human evidence, 2007–2013. Environ Health Perspect 122:775–786
Petrie A, Watson P (2013) Statistics for veterinary and animal science, 3rd edn. Wiley-Blackwell Publishing Ltd, Oxford, pp 121–125
Reddy P, Zheng W, Liu K (2010) Mechanisms maintaining the dormancy and survival of mammalian primordial follicles. Trends Endocrinol Metab 21:96–103
Salvati G, Genovesi G, Marcellini L, Paolini P, De Nuccio I, Pepe M, Re M (1996) Effects of Panax Ginseng C.A. Meyer saponins on male fertility. Panminerva Med 38:249–254
Schonfelder G, Wittfoht W, Hopp H, Talsness CE, Paul M, Chahoud I (2002) Parent bisphenol A accumulation in the human maternal-fetal-placental unit. Environ Health Perspect 110:A703–A707
Shultz VD, Phillips S, Sar M, Foster PM, Gaido KW (2001) Altered gene profiles in fetal rat testes after in utero exposure to di(n-butyl) phthalate. Toxicol Sci 64:233–242
SPSS (2009) PASW Statistics for Windows, Version 18.0. Chicago: SPSS Inc.
Strauss JF (2014) The synthesis and metabolism of steroid hormones. In: Strauss JF III (ed) Yen & Jaffe’s Reproductive Endocrinology (Seventh Edition). Elsevier Saunders, Philadelphia, pp 66–92.e63
Stump DG, Beck MJ, Radovsky A, Garman RH, Freshwater LL, Sheets LP, Marty MS, Waechter JM Jr, Dimond SS, Van Miller JP, Shiotsuka RN, Beyer D, Chappelle AH, Hentges SG (2010) Developmental neurotoxicity study of dietary bisphenol A in Sprague-Dawley rats. Toxicol Sci 115:167–182
Susiarjo M, Hassold TJ, Freeman E, Hunt PA (2007) Bisphenol A exposure in utero disrupts early oogenesis in the mouse. PLoS Genet 3:e5
Svechnikova I, Svechnikov K, Soder O (2007) The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats. J Endocrinol 194:603–609
Wang L, Hao J, Hu J, Pu J, Lü Z, Zhao L, Wang Q, Yu Q, Wang Y, Li G (2012) Protective effects of ginsenosides against bisphenol A-induced cytotoxicity in 15P-1 sertoli cells via extracellular signal-regulated kinase 1/2 signalling and antioxidant mechanisms. Basic Clin Pharmacol Toxicol 111:42–49
Woodruff TJ, Zota AR, Schwartz JM (2011) Environmental chemicals in pregnant women in the United States: NHANES 2003–2004. Environ Health Perspect 119:878–885
Yang M, Lee H-S, Hwang M-W, Jin M (2014) Effects of Korean red ginseng (Panax Ginseng Meyer) on bisphenol A exposure and gynecologic complaints: single blind, randomized clinical trial of efficacy and safety. BMC Complement Altern Med 14:265
Yang Y, Qiu S, Qian L, Tian Y, Chen Y, Bi L, Chen W (2017) OCF can repress tumor metastasis by inhibiting epithelial–mesenchymal transition involved in PTEN/PI3K/AKT pathway in lung cancer cells. PLoS One 12:e0174021
Zhang H-Q, Zhang X-F, Zhang L-J, Chao H-H, Pan B, Feng Y-M, Li L, Sun X-F, Shen W (2011) Fetal exposure to bisphenol A affects the primordial follicle formation by inhibiting the meiotic progression of oocytes. Mol Biol Rep 39:5651–5657
Acknowledgements
The authors extended their appreciation to the Deanship of Scientific Research at King Saud University for funding this work through the research group project (# RG-1438-018).
Funding
Deanship of Scientific Research at King Saud University for funding this work through the research group project # RG-1438-018.
Author information
Authors and Affiliations
Contributions
All authors shared in the design and implementation of this study. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Additional information
Responsible editor: Philippe Garrigues
Electronic supplementary material
ESM 1
(DOCX 19 kb)
Rights and permissions
About this article
Cite this article
Saadeldin, I.M., Hussein, M.A., Suleiman, A.H. et al. Ameliorative effect of ginseng extract on phthalate and bisphenol A reprotoxicity during pregnancy in rats. Environ Sci Pollut Res 25, 21205–21215 (2018). https://doi.org/10.1007/s11356-018-2299-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-018-2299-1