Effect of early postnatal exposure to 17α-ethinylestradiol on female rat reproductive physiology

Springer Science and Business Media LLC - Tập 13 - Trang 101-108 - 2021
Kevin Poissenot1, Chantal Moussu1, Alain Reymond2, Pierre Dorfman2, Matthieu Keller1
1Physiologie de La Reproduction & Des Comportements, UMR INRAE/CNRS/Université de Tours/IFCE, Nouzilly, France
2CEIA/PROTEOMIS, Bruxelles, Belgium

Tóm tắt

17α-Ethinylestradiol (EE2) is a synthetic compound used as an oral contraceptive in birth control pills. EE2 is a major contaminant in aquatic environments. It is considered an endocrine-disrupting chemical due to its oestrogenic activity. This study investigates the effect of repeated exposure to EE2 at a dose of 1 µg/kg·(body weight)/day on reproductive function and metabolism. Female Sprague–Dawley rats were subcutaneously injected with EE2 at a dose of 1 µg/kg·(body weight)/day from postnatal day 1 until postnatal day 5, which corresponds to a highly sensitive period of neuroendocrine system organisation. The anogenital distance, body weight and blood levels of insulin and glucose of EE2-treated female rats were not different from those of control rats. These results indicate that growth and glucose metabolism were unaffected by treatment. In contrast, vaginal opening occurred significantly earlier in EE2-treated females than in control females. In adulthood, these females present an alteration of their oestrous cyclicity, characterised by persistent vaginal oestrus. Moreover, treated females showed altered uterine and ovarian morphology associated with lower circulating levels of oestradiol and progesterone. These results indicate precocious onset of puberty and dysfunction of the reproductive organs. Therefore, early postnatal exposure to EE2 at a dose of 1 µg/kg·bw/d has delayed adverse effects on reproductive function.

Tài liệu tham khảo

Wilhelm D, Palmer S, Koopman P (2007) Sex determination and gonadal development in mammals. Physiol Rev 87:1–28. https://doi.org/10.1152/physrev.00009.2006 Yao Hung-Chang H (2005) The pathway to femaleness: current knowledge on embryonic development of the ovary. Mol Cell Endocrinol 230:87–93. https://doi.org/10.1016/j.mce.2004.11.003.The Kashimada K, Koopman P (2010) Sry: The master switch in mammalian sex determination. Development 137:3921–3930. https://doi.org/10.1242/dev.048983 Lee HR, Jeung EB, Cho MH, Kim TH, Leung PCK, Choi KC (2013) Molecular mechanism(s) of endocrine-disrupting chemicals and their potent oestrogenicity in diverse cells and tissues that express oestrogen receptors. J Cell Mol Med 17:1–11. https://doi.org/10.1111/j.1582-4934.2012.01649.x Welshons WV, Nagel SC, Vom Saal FS (2006) Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology 147:56–69. https://doi.org/10.1210/en.2005-1159 Larcher S, Yargeau V (2013) Biodegradation of 17α-ethinylestradiol by heterotrophic bacteria. Environ Pollut 173:17–22. https://doi.org/10.1016/j.envpol.2012.10.028 Johnson AC, Williams RJ (2004) A model to estimate influent and effluent concentrations of estradiol, estrone, and ethinylestradiol at sewage treatment works. Environ Sci Technol 38:3649–3658. https://doi.org/10.1021/es035342u Aris AZ, Shamsuddin AS, Praveena SM (2014) Occurrence of 17α-ethynylestradiol (EE2) in the environment and effect on exposed biota: a review. Environ Int Elsevier Ltd 69:104–119. https://doi.org/10.1016/j.envint.2014.04.011 Bilal M, Iqbal HMN (2019) Persistence and impact of steroidal estrogens on the environment and their laccase-assisted removal. Sci Total Environ 690:447–459. https://doi.org/10.1016/j.scitotenv.2019.07.025 Haapakoski M, Hardenbol A, Matson K (2018) Exposure to chemical cues from predator-exposed conspecifics increases reproduction in a wild rodent. Sci Rep Springer, US. https://doi.org/10.1038/s41598-018-35568-0 França JF De, Pickler TB, Jozala AF, Alves C, Batista BL, Pedron T (2020) Determination of 17 α -ethinylestradiol and toxic metals in surface waters , and estimation of daily intake. Environ Monit Assess 1–10 The European Parlament and the Council of the European Union (2013) Directives of 12 August 2013 amending Directives 2000/60/EC and 2008/105/EC as regards priority substances in the field of water policy. Off. J. Eur. Union. p 1–17. http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex:32013L0039 Loos R, Marinov D, Sanseverino I, Napierska D, Lettieri T (2018) Review of the 1st watch list under the water framework directive and recommendations for the 2nd watch list [Internet]. Res. Cent, Jt. https://doi.org/10.2760/614367 Freyberger A, Wilson V, Weimer M, Tan S, Tran HS, Ahr HJ (2010) Assessment of a robust model protocol with accelerated throughput for a human recombinant full length estrogen receptor-α binding assay: protocol optimization and intralaboratory assay performance as initial steps towards validation. Reprod Toxicol 30:50–59. https://doi.org/10.1016/j.reprotox.2010.01.001 Dickson RB, Eisenfield AJ (1981) 17Α-ethinyl estradiol is more potent than estradiol in receptor interactions with isolated hepatic parenchymal cells. Endocrinology 108:1511–1518. https://doi.org/10.1210/endo-108-4-1511 Sheehan DM, Branham WS (1987) Dissociation of estrogen-induced uterine growth and ornithine decarboxylase activity in the postnatal rat. Teratog Carcinog Mutagen 7:411–422. https://doi.org/10.1002/tcm.1770070408 Hong H, Branham WS, Dial SL, Moland CL, Fang H, Shen J et al (2012) Rat α-fetoprotein binding affinities of a large set of structurally diverse chemicals elucidated the relationships between structures and binding affinities. Chem Res Toxicol 25:2553–2566. https://doi.org/10.1021/tx3003406 Godsland IF, Walton C, Felton C, Proudler A, Patel A, Wynn V (2014) Insulin resistance, secretion, and metabolism in users of oral contraceptives. 74:64–70 Kojima T, Lindheim SR, Duffy DM, Vijod MA, Stanczyk FZ, Lobo RA (1993) Insulin sensitivity is decreased in normal women by doses of ethinyl estradiol used in oral contraceptives. Am J Obstetr Gynecol Mosby 169:1540–1544. https://doi.org/10.1016/0002-9378(93)90432-I de Oliveira CAR, dos Reis Araujo T, de Aguiar GS, da Silva Junior JA, Vettorazzi JF, Freitas IN et al (2019) Combined oral contraceptive in female mice causes hyperinsulinemia due to β-cell hypersecretion and reduction in insulin clearance. J Steroid Biochem Mol Biol 190:54–63. https://doi.org/10.1016/j.jsbmb.2019.03.018 Stanczyk FZ, Archer DF, Bhavnani BR (2013) Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception 87:706–727. https://doi.org/10.1016/j.contraception.2012.12.011 NTP (2010) Multigenerational reproductive toxicology study in Sprague-Dawley rats Ryan BC, Hotchkiss AK, Crofton KM, Earl Gray J (2009) In utero and lactational exposure to bisphenol A, in contrast to ethinyl estradiol, does not alter sexually dimorphic behavior, puberty, fertility, and anatomy of female LE rats. Toxicol Sci 114:133–148. https://doi.org/10.1093/toxsci/kfp266 Alexanderson C, Eriksson E, Stener-Victorin E, Lönn M, Holmáng A (2009) Early postnatal oestradiol exposure causes insulin resistance and signs of inflammation in circulation and skeletal muscle. J Endocrinol 201:49–58. https://doi.org/10.1677/JOE-08-0534 Ma Y, Xia W, Wang DQ, Wan YJ, Xu B, Chen X et al (2013) Hepatic DNA methylation modifications in early development of rats resulting from perinatal BPA exposure contribute to insulin resistance in adulthood. Diabetologia 56:2059–2067. https://doi.org/10.1007/s00125-013-2944-7 Derouiche L, Keller M, Martini M, Duittoz AH, Pillon D (2015) Developmental exposure to ethinylestradiol affects reproductive physiology, the GnRH neuroendocrine network and behaviors in female mouse. Front Neurosci 9:1–14. https://doi.org/10.3389/fnins.2015.00463 Shirota M, Kawashima J, Nakamura T, Kamiie J, Shirota K, Yoshida M (2015) Dose-dependent acceleration in the delayed effects of neonatal oral exposure to low-dose 17 alpha-ethynylestradiol on reproductive functions in female Sprague-Dawley rats. J Toxicol Sci 40:727–738 Shiorta M, Kawashima J, Nakamura T, Ogawa Y, Kamiie J, Yasuno K et al (2012) Delayed effects of single neonatal subcutaneous exposure of low-dose 17α-ethynylestradiol on reproductive function in female rats. J Toxicol Sci 37:681–690. https://doi.org/10.2131/jts.37.681 Takahashi M, Inoue K, Morikawa T, Matsuo S, Hayashi S, Tamura K et al (2014) Early indicators of delayed adverse effects in female reproductive organs in rats receiving neonatal exposure to 17alpha-ethynylestradiol. J Toxicol Sci 39:775–784. https://doi.org/10.2131/jts.39.775 Kevenaar ME, Meerasahib MF, Kramer P, Van De Lang-Born BMN, De Jong FH, Groome NP et al (2006) Serum anti-Müllerian hormone levels reflect the size of the primordial follicle pool in mice. Endocrinology 147:3228–3234. https://doi.org/10.1210/en.2005-1588 Rodriguez P, Fernández-Galaz C, Tejero A (1993) Controlled neonatal exposure to estrogens: a suitable tool for reproductive aging studies in the female rat. Biol Reprod 49:387–392. https://doi.org/10.1095/biolreprod49.2.387 Barnham W, Zehr D, Chen J, Sheehan D (1988) Uterine abnormalities in rats exposed neonatally to diethylstilbestrol, ethynylestradiol, or clomiphene citrate. Toxicology 51:201–212 Newbold RR, Jefferson WN, Padilla-Banks E, Haseman J (2004) Developmental exposure to diethylstilbestrol (DES) alters uterine response to estrogens in prepubescent mice: Low versus high dose effects. Reprod Toxicol 18:399–406. https://doi.org/10.1016/j.reprotox.2004.01.007 Wood GA, Fata JE, Watson KLM, Khokha R (2007) Circulating hormones and estrous stage predict cellular and stromal remodeling in murine uterus. Reproduction 133:1035–1044. https://doi.org/10.1530/REP-06-0302 Fernández M, Bianchi M, Lux-Santos V, Libertun C (2009) Neonatal exposure to bisphenol A alters reproductive parameters and gonadotropin releasing hormone signaling in female rats. Environ Health Perspect 117:757–762. https://doi.org/10.1289/ehp.0800267 Losa SM, Todd KL, Sullivan AW, Cao J, Mickens JA, Patisaul HB (2011) Neonatal exposure to genistein adversely impacts the ontogeny of hypothalamic kisspeptin signaling pathways and ovarian development in the peripubertal female rat. Reprod Toxicol 31:280–289. https://doi.org/10.1016/j.reprotox.2010.10.002 Bateman HL, Patisaul HB (2008) Disrupted female reproductive physiology following neonatal exposure to phytoestrogens or estrogen specific ligands is associated with decreased GnRH activation and kisspeptin fiber density in the hypothalamus. NeuroToxicology 29:988–997. https://doi.org/10.1016/j.neuro.2008.06.008