Skip to main content
SpringerLink
Log in

Dioxin-induced fetal growth retardation: the role of a preceding attenuation in the circulating level of glucocorticoid

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Exposure of pregnant rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at a low dose causes developmental disorders such as growth retardation and sexual immaturity in their pups. Our previous studies have demonstrated that TCDD attenuates the expression of pituitary luteinizing hormone in fetuses, resulting in the impairment of sexual behavior after they reach maturity. In this study, we focused on growth disturbance and investigated whether TCDD affects the expression of growth hormone (GH), another pituitary hormone which is essential for normal development in perinatal pups. The result showed that maternal exposure to TCDD (1 µg/kg) at gestational day (GD) 15 reduced the fetal expression of GH from the onset at GD18. In accordance with this, TCDD attenuated the pup weight during the perinatal period. We then examined the effect of TCDD on the serum concentration of corticosterone, which plays a key role in the proliferation of GH-producing cells, and found that TCDD reduces the circulating level of corticosterone in the mothers at GD18 and the male fetuses at GD19. The reduction in fetuses seems to be due to increased inactivation rather than reduced synthesis, because TCDD induces the fetal expression of hepatic enzymes participating in the metabolism of glucocorticoids without changing the expression of steroidogenic proteins in the pituitary–adrenal axis. Supplying corticosterone to TCDD-exposed mothers restored or tended to restore a TCDD-induced reduction in pup weight as well as the levels of pituitary GH mRNA and serum GH. These results suggest that TCDD lowers GH expression and growth retardation owing, at least partially, to a reduction in the circulating level of glucocorticoid in pregnant mothers and their fetuses.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. T.A. Gasiewicz, in 18.5 TCDD and other acnegenic materials, ed. by W.J. Hayes Jr., E.R. Laws. Handbook of pesticide toxicology, vol. 3, Classes of pesticides (Academic Press, San Diego, 1991), pp. 1217–1269

  2. J.R. Olson, Metabolism and disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin in guinea pigs. Toxicol. Appl. Pharmacol. 85, 263–273 (1986)

    Article  PubMed  CAS  Google Scholar 

  3. J.L. Pirkle, W.H. Wolfe, D.G. Patterson, L.L. Needham, J.E. Michalek, J.C. Miner, M.R. Peterson, D.L. Phillips, Estimates of the half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Vietnam veterans of Operation Ranch Hand. J. Toxicol. Environ. Health 27, 165–171 (1989)

    Article  PubMed  CAS  Google Scholar 

  4. B.D. Kerger, H.-W. Leung, P. Scott, D.J. Paustenbach, L.L. Needham, D.G. Patterson, P.M. Gerthoux Jr, P. Mocarelli, Age- and concentration-dependent elimination half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso children. Environ. Health Perspect. 114, 1596–1602 (2006)

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. A. Geusau, S. Schmaldienst, K. Derfler, O. Päpke, K. Abraham, Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: kinetics and trials to enhance elimination in two patients. Arch. Toxicol. 76, 316–325 (2002)

    Article  PubMed  CAS  Google Scholar 

  6. M. Van den Berg, J. De Jongh, H. Poiger, J.R. Olson, The toxicokinetics and metabolism of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) and their relevance for toxicity. Crit. Rev. Toxicol. 24, 1–74 (1994)

    Article  PubMed  Google Scholar 

  7. C.H. Hurst, M.J. DeVito, R.W. Setzer, L.S. Birnbaum, Acute administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in pregnant Long Evans rats: association of measured tissue concentrations with developmental effects. Toxicol. Sci. 53, 411–420 (2000)

    Article  PubMed  CAS  Google Scholar 

  8. T. Tanida, K. Warita, K. Ishihara, S. Fukui, T. Mitsuhashi, T. Sugawara, Y. Tabuchi, T. Nanmori, W.M. Qi, T. Inamoto, T. Yokoyama, H. Kitagawa, N. Hoshi, Fetal and neonatal exposure to three typical environmental chemicals with different mechanisms of action: mixed exposure to phenol, phthalate, and dioxin cancels the effects of sole exposure on mouse midbrain dopaminergic nuclei. Toxicol. Lett. 189, 40–47 (2009)

    Article  PubMed  CAS  Google Scholar 

  9. L.E. Gray Jr, J.S. Ostby, In utero 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters reproductive morphology and function in female rat offspring. Toxicol. Appl. Pharmacol. 133, 285–294 (1995)

    Article  PubMed  CAS  Google Scholar 

  10. R.E. Peterson, H.M. Theobald, G.L. Kimmel, Developmental and reproductive toxicity of dioxins and related compounds: cross-species comparisons: cross-species comparisons. Crit. Rev. Toxicol. 23, 283–335 (1993)

    Article  PubMed  CAS  Google Scholar 

  11. M. Nishijo, J.I. Kuriwaki, E. Hori, K. Tawara, H. Nakagawa, H. Nishijo, Effects of maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on fetal brain growth and motor and behavioral development in offspring rats. Toxicol. Lett. 173, 41–47 (2007)

    Article  PubMed  CAS  Google Scholar 

  12. T.A. Mably, R.W. Moore, R.E. Peterson, In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin. 1. Effects on androgenic status. Toxicol. Appl. Pharmacol. 114, 97–107 (1992)

    Article  PubMed  CAS  Google Scholar 

  13. D.L. Bjerke, R.E. Peterson, Reproductive toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male rats: different effects of in utero versus lactational exposure. Toxicol. Appl. Pharmacol. 127, 241–249 (1994)

    Article  PubMed  CAS  Google Scholar 

  14. B.W. Seo, B.E. Powers, J.J. Widholm, S.L. Schantz, Radial arm maze performance in rats following gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Neurotoxicol. Teratol. 22, 511–519 (2000)

    Article  PubMed  CAS  Google Scholar 

  15. J. Mutoh, J. Taketoh, K. Okamura, T. Kagawa, T. Ishida, Y. Ishii, H. Yamada, Fetal pituitary gonadotropin as an initial target of dioxin in its impairment of cholesterol transportation and steroidogenesis in rats. Endocrinology 147, 927–936 (2006)

    Article  PubMed  CAS  Google Scholar 

  16. J. Taketoh, J. Mutoh, T. Takeda, T. Ogishima, S. Takeda, Y. Ishii, T. Ishida, H. Yamada, Suppression of fetal testicular cytochrome P450 17 by maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin: a mechanism involving an initial effect on gonadotropin synthesis in the pituitary. Life Sci. 80, 1259–1267 (2007)

    Article  PubMed  CAS  Google Scholar 

  17. T. Takeda, Y. Matsumoto, T. Koga, J. Mutoh, Y. Nishimura, T. Shimazoe, Y. Ishii, T. Ishida, H. Yamada, Maternal exposure to dioxin disrupts gonadotropin production in fetal rats and imprints defects in sexual behavior. J. Pharmacol. Exp. Ther. 329, 1091–1099 (2009)

    Article  PubMed  CAS  Google Scholar 

  18. T. Takeda, M. Fujii, J. Taura, Y. Ishii, H. Yamada, Dioxin silences gonadotropin expression in perinatal pups by inducing histone deacetylases: a new insight into the mechanism for the imprinting of sexual immaturity by dioxin. J. Biol. Chem. 287, 18440–18450 (2012)

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. T. Takeda, M. Fujii, Y. Hattori, M. Yamamoto, T. Shimazoe, Y. Ishii, M. Himeno, H. Yamada, Maternal exposure to dioxin imprints sexual immaturity of the pups through fixing the status of the reduced expression of hypothalamic gonadotropin-releasing hormone. Mol. Pharmacol. 85, 74–82 (2014)

    Article  PubMed  CAS  Google Scholar 

  20. K. De Jesus, X. Wang, J.L. Liu, A general IGF-I overexpression effectively rescued somatic growth and bone deficiency in mice caused by growth hormone receptor knockout. Growth Factors 27, 438–447 (2009)

    Article  PubMed  Google Scholar 

  21. K. Sjögren, Y.M. Bohlooly, B. Olsson, K. Coschigano, J. Törnell, S. Mohan, O.G.P. Isaksson, G. Baumann, J. Kopchhick, C. Ohlsson, Disproportional skeletal growth and markedly decreased bone mineral content in growth hormone receptor −/− mice. Biochem. Biophys. Res. Commun. 267, 603–608 (2000)

    Article  PubMed  Google Scholar 

  22. E. Li, D.H. Kim, M. Cai, S. Lee, Y. Kim, E. Lim, J.H. Ryu, T.G. Unterman, S. Park, Hippocampus-dependent spatial learning and memory are impaired in growth hormone-deficient spontaneous dwarf rats. Endocr. J. 58, 257–267 (2011)

    Article  PubMed  CAS  Google Scholar 

  23. R.G. Ahmed, Perinatal TCDD exposure alters developmental neuroendocrine system. Food Chem. Toxicol. 49, 1276–1284 (2011)

    Article  PubMed  CAS  Google Scholar 

  24. G. Cabello, C. Wrutniak, Thyroid hormone and growth: relationships with growth hormone effects and regulation. Reprod. Nutr. Dev. 29, 387–402 (1989)

    Article  PubMed  CAS  Google Scholar 

  25. B.-W. Seo, M.-H. Li, L.G. Hansen, R.W. Moore, R.J.Z. Peterson, S.L. Schantz, Effects of gestational and lactational exposure to coplanar polychlorinated biphenyl (PCB) congners or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on thyroid hormone concentrations in weanling rats. Toxicol. Lett. 78, 253–262 (1995)

    Article  PubMed  CAS  Google Scholar 

  26. N. Nishimura, J. Yonemoto, Y. Miyabara, M. Sato, C. Tohyama, Rat thyroid hyperplasia induced by gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Endocrinology 144, 2075–2083 (2003)

    Article  PubMed  CAS  Google Scholar 

  27. N. Nishimura, J. Yonemoto, H. Nishimura, S. Ikushiro, C. Tohyama, Disruption of thyroid hormone homeostasis at weaning of Holtzman rats by lactational but not in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Sci. 85, 607–614 (2005)

    Article  PubMed  CAS  Google Scholar 

  28. H. Nogami, S. Hisano, Functional maturation of growth hormone cells in the anterior pituitary gland of the fetus. Growth hormon. IGF Res. 18, 379–388 (2008)

    Article  CAS  Google Scholar 

  29. T.E. Porter, Regulation of pituitary somatotroph differentiation by hormones of peripheral endocrine glands. Domest. Anim. Endocrinol. 29, 52–62 (2005)

    Article  PubMed  CAS  Google Scholar 

  30. H. Nogami, K. Inoue, K. Kawamura, Involvement of glucocorticoid-induced factor(s) in the stimulation of growth hormone expression in the fetal rat pituitary gland in vitro. Endocrinology 138, 1810–1815 (1997)

    PubMed  CAS  Google Scholar 

  31. H. Nogami, T. Tachibana, Dexamethasone induces advanced growth hormone expression in the fetal rat pituitary gland in vivo. Endocrinology 132, 517–523 (1993)

    PubMed  CAS  Google Scholar 

  32. Y. Matsumoto, T. Ishida, T. Takeda, T. Koga, M. Fujii, Y. Ishii, Y. Fujimura, D. Miura, H. Wariishi, H. Yamada, Maternal exposure to dioxin reduces hypothalamic but not pituitary metabolome in fetal rats: a possible mechanism for a fetus-specific reduction in steroidogenesis. J. Toxicol. Sci. 35, 365–373 (2010)

    Article  PubMed  CAS  Google Scholar 

  33. J. Lépine, O. Bernard, M. Plante, B. Têtu, G. Pelletier, F. Labrie, A. Bélanger, C. Guillemette, Specificity and regioselectivity of the conjugation of estradiol, estrone, and their catecholestrogen and methoxyestrogen metabolites by human uridine diphospho-glucuronosyltransferases expressed in endometrium. J. Clin. Endocrinol. Metab. 89, 5222–5232 (2004)

    Article  PubMed  Google Scholar 

  34. K. Itäaho, P.I. Mackenzie, S. Ikushiro, J.O. Miners, M. Finel, The configuration of the 17-hydroxy group variably influences the glucuronidation of beta-estradiol and epiestradiol by human UDP-glucuronosyltransferases. Drug Metab. Dispos. 36, 2307–2315 (2008)

    Article  PubMed  Google Scholar 

  35. L. Kornel, S. Miyabo, Z. Saito, R.-W. Cha, F.-T. Wu, Corticosteroids in human blood. VIII. Cortisol metabolites in plasma of normotensive subjects and patients with essential hypertension. J. Clin. Endocrinol. Metab. 40, 949–958 (1975)

    Article  PubMed  CAS  Google Scholar 

  36. B.P. Schimmer, J.W. Funder, 42 ACTH, adrenal steroids, and pharmacology of the adrenal cortex, in Goodman and Gilman’s the pharmacological basis of therapeutics, 12th edn., ed. by L.L. Brunton, B.A. Chabner, B.C. Knollmann (McGraw-Hill Professional, New York, 2011), pp. 1209–1235

    Google Scholar 

  37. M.J. Nyirenda, R.S. Lindsay, C.J. Kenyon, A. Burchell, J.R. Seckl, Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. J. Clin. Invest. 101, 2174–2181 (1998)

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. B.C. Bingham, C.S. Sheela Rani, A. Frazer, R. Strong, D.A. Morilak, Exogenous prenatal corticosterone exposure mimics the effects of prenatal stress on adult brain stress response systems and fear extinction behavior. Psychoneuroendocrinology 38, 2746–2757 (2013)

    Article  PubMed  CAS  Google Scholar 

  39. G. Mazziotti, A. Giustina, Glucocorticoids and the regulation of growth hormone secretion. Nat. Rev. Endocrinol. 9, 265–276 (2013)

    Article  PubMed  CAS  Google Scholar 

  40. A. Giustina, W.B. Wehrenberg, The role of glucocorticoids in the regulation of growth hormone secretion: mechanisms and clinical significance. Trends Endocrinol. Metab. 3, 306–311 (1992)

    Article  PubMed  CAS  Google Scholar 

  41. H. Vakili, Y. Jin, J.I. Nagy, P.A. Cattini, Transgenic mice expressing the human growth hormone gene provide a model system to study human growth hormone synthesis and secretion in non-tumor-derived pituitary cells: differential effects of dexamethasone and thyroid hormone. Mol. Cell. Endocrinol. 345, 48–57 (2011)

    Article  PubMed  CAS  Google Scholar 

  42. W.B. Wehrenberg, P.J. Bergman, L. Stagg, J. Ndon, A. Giustina, Glucocorticoid inhibition of growth in rats: partial reversal with somatostatin antibodies. Endocrinology 127, 2705–2708 (1990)

    Article  PubMed  CAS  Google Scholar 

  43. L. Li, Z.Q. Li, C.H. Deng, M.R. Ning, H.Q. Li, S.S. Bi, T.Y. Zhou, W. Lu, A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats. Acta Pharmacol. Sin. 33, 127–136 (2012)

    Article  PubMed  PubMed Central  Google Scholar 

  44. N. Ejiri, K. Katayama, K. Doi, Induction of CYP3A1 by dexamethasone and pregnenolone-16alpha-carbonitrile in pregnant rat and fetal livers and placenta. Exp. Toxicol. Pathol. 54, 273–279 (2003)

    Article  PubMed  CAS  Google Scholar 

  45. T. Takeda, Y. Hattori, M. Fujii, J. Taura, Y. Ishii, H. Yamada, The gender-specific effect of maternal exposure to dioxin on fetal steroidogenesis in the adrenal gland. Fukuoka Acta Med. 104, 143–151 (2013)

    PubMed  CAS  Google Scholar 

  46. M.J. Blake, L. Castro, J.S. Leeder, G.L. Kearns, Ontogeny of drug metabolizing enzymes in the neonate. Semin. Fetal Neonatal Med. 10, 123–138 (2005)

    Article  PubMed  Google Scholar 

  47. Z. Krozowski, K.X. Li, K. Koyama, R.E. Smith, V.R. Obeyesekere, A. Stein-Oakley, H. Sasano, C. Coulter, T. Cole, K.E. Sheppard, The type I and type II 11beta-hydroxysteroid dehydrogenase enzymes. J. Steroid Biochem. Mol. Biol. 69, 391–401 (1999)

    Article  PubMed  CAS  Google Scholar 

  48. M. Weinstock, Alterations induced by gestational stress in brain morphology and behaviour of the offspring. Prog. Neurobiol. 65, 427–451 (2001)

    Article  PubMed  CAS  Google Scholar 

  49. O.R. Vaughan, A.N. Sferruzzi-Perri, A.L. Fowden, Maternal corticosterone regulates nutrient allocation to fetal growth in mice. J. Physiol. 590, 5529–5540 (2012)

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. D.J. Auyeung, F.K. Kessler, J.K. Ritter, Mechanism of rat UDP-glucuronosyltransferase 1A6 induction by oltipraz: evidence for a contribution of the Aryl hydrocarbon receptor pathway. Mol. Pharmacol. 63, 119–127 (2003)

    Article  PubMed  CAS  Google Scholar 

  51. N. Nishimura, J. Yonemoto, Y. Miyabara, Y. Fujii-Kuriyama, C. Tohyama, Altered thyroxin and retinoid metabolic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin in aryl hydrocarbon receptor-null mice. Arch. Toxicol. 79, 260–267 (2004)

    Article  PubMed  Google Scholar 

  52. A. Fujisawa-Sehara, K. Sogawa, M. Yamane, Y. Fujii-Kuriyama, Characterization of xenobiotic responsive elements upstream from the drug-metabolizing cytochrome P-450c gene: a similarity to glucocorticoid regulatory elements. Nucleic Acids Res. 15, 4179–4191 (1987)

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. J. Wilson, Growth hormone modulation of liver drug metabolic enzyme activity in the rat. Specificity of the hormone effect. Proc. Soc. Exp. Biol. Med. 143, 978–985 (1973)

    Article  PubMed  CAS  Google Scholar 

  54. D.J. Waxman, C. O’Connor, Growth hormone regulation of sex-dependent liver gene expression. Mol. Endocrinol. 20, 2613–2629 (2006)

    Article  PubMed  CAS  Google Scholar 

  55. Y. Yamazoe, M. Shimada, N. Murayama, S. Kawano, R. Kato, The regulation by growth hormone of microsomal testosterone 6β-hydroxylase in male rat liver. J. Biochem. 100, 1095–1097 (1986)

    PubMed  CAS  Google Scholar 

  56. S.K. Lu, S.M. Callahan, L.J. Brunner, Suppression of hepatic CYP3A1/2 and CYP2C11 by cyclosporine is not mediated by altering growth hormone levels. J. Pharmacol. Exp. Ther. 305, 331–337 (2003)

    Article  PubMed  CAS  Google Scholar 

  57. C. Lee, D.S. Riddick, Aryl hydrocarbon receptor-dependence of dioxin’s effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components. Can. J. Physiol. Pharmacol. 90, 1354–1363 (2012)

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by Grants from the Japan Society for the Promotion of Science [Scientific Research (S) 24221004] and the Ministry of Health, Labour and Welfare, Japan [Research on Food Safety (H24-Designated Research-014)].

Conflict of interest

The authors declare that there are no conflicts of interest.

Author information

Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Yukiko Hattori, Tomoki Takeda, Misaki Fujii, Junki Taura, Yuji Ishii & Hideyuki Yamada

Authors
  1. Yukiko Hattori
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomoki Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Misaki Fujii
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Junki Taura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuji Ishii
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hideyuki Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hideyuki Yamada.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 105 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hattori, Y., Takeda, T., Fujii, M. et al. Dioxin-induced fetal growth retardation: the role of a preceding attenuation in the circulating level of glucocorticoid. Endocrine 47, 572–580 (2014). https://doi.org/10.1007/s12020-014-0257-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-014-0257-3

Keywords

Search

Navigation