Opposite effects of high- and low-dose di-(2-ethylhexyl) phthalate (DEHP) exposure on puberty onset, oestrous cycle regularity and hypothalamic kisspeptin expression in female rats
Zhen Yu A , Fan Wang A , Junyong Han A , Rongmei Lu B , Qian Li C , Liangchun Cai B , Bishuang Li C , Jinyan Chen A , Kun Wang A , Wenjin Lin A , Qinghua Lin A , Gang Chen
A B D and Junping Wen B D
+ Author Affiliations
- Author Affiliations
A Fujian Key Laboratory of Medical Measurement, Fujian Academy of Medical Sciences, Fuzhou 350001, China.
B Department of Endocrinology, Fujian Provincial Hospital, Fuzhou 350001, China.
C Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350001, China.
D Corresponding authors: Emails: chengangfj@163.com; junpingwen@163.com
Reproduction, Fertility and Development 32(6) 610-618 https://doi.org/10.1071/RD19024
Submitted: 15 January 2019 Accepted: 29 October 2019 Published: 11 February 2020
Abstract
Di-(2-ethylhexyl) phthalate (DEHP) is ubiquitous in the environment and has been proposed to lead to reproductive disruption. In this study, we systematically investigated the effects of different doses of DEHP exposure on female hypothalamic–pituitary–gonadal axis development. Female Sprague–Dawley rats were gavaged with vehicle (corn oil) or DEHP (5 or 500 mg kg–1 day–1) during postnatal Days (PNDs) 22–28 or PNDs 22–70. Results demonstrated that the low and high doses of DEHP exerted opposite effects on puberty onset, circulating luteinising hormone, serum oestradiol and progesterone levels, with the low dose (5 mg kg–1) promoting and the high dose (500 mg kg–1) inhibiting these parameters. Significant dose-related differences were also found in the D500 group with longer oestrous cycle duration, lower ovarian/bodyweight ratio, fewer corpus lutea and more abnormal ovarian stromal tissue in comparison with the oil or D5 groups. Molecular data showed that the hypothalamic Kiss1 mRNA expression in the anteroventral periventricular but not in the arcuate nucleus significantly decreased in the D500 rats and increased in the D5 rats relative to the rats in the oil group. These findings suggested that the kisspeptin system is a potential target for DEHP to disrupt reproductive development and function.
Additional keywords: AVPV, gonadotrophin-releasing hormone, hypothalamic–pituitary–gonadal axis, neuroendocrinological development, prepubertal exposure, reproductive function.
References
Albert, O., Nardelli, T. C., Lalancette, C., Hales, B. F., and Robaire, B. (2018). Effects of in utero and lactational exposure to new generation green plasticizers on adult male rats: a comparative study with di(2-ethylhexyl) phthalate. Toxicol. Sci. 164, 129–141.| Effects of in utero and lactational exposure to new generation green plasticizers on adult male rats: a comparative study with di(2-ethylhexyl) phthalate.Crossref | GoogleScholarGoogle Scholar | 29945229PubMed |
Andrade, A. J., Grande, S. W., Talsness, C. E., Gericke, C., Grote, K., Golombiewski, A., Sterner-Kock, A., and Chahoud, I. (2006). A dose response study following in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP): reproductive effects on adult male offspring rats. Toxicology 228, 85–97.
| A dose response study following in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP): reproductive effects on adult male offspring rats.Crossref | GoogleScholarGoogle Scholar | 16996189PubMed |
Bellingham, M., Fowler, P. A., Amezaga, M. R., Rhind, S. M., Cotinot, C., Mandon-Pepin, B., Sharpe, R. M., and Evans, N. P. (2009). Exposure to a complex cocktail of environmental endocrine-disrupting compounds disturbs the kisspeptin/GPR54 system in ovine hypothalamus and pituitary gland. Environ. Health Perspect. 117, 1556–1562.
| Exposure to a complex cocktail of environmental endocrine-disrupting compounds disturbs the kisspeptin/GPR54 system in ovine hypothalamus and pituitary gland.Crossref | GoogleScholarGoogle Scholar | 20019906PubMed |
Bohlen, T. M., Silveira, M. A., Zampieri, T. T., Frazao, R., and Donato, J. J. (2016). Fatness rather than leptin sensitivity determines the timing of puberty in female mice. Mol. Cell. Endocrinol. 423, 11–21.
| Fatness rather than leptin sensitivity determines the timing of puberty in female mice.Crossref | GoogleScholarGoogle Scholar | 26762764PubMed |
Burger, L. L., Haisenleder, D. J., and Marshall, J. C. (2011). GnRH pulse frequency differentially regulates steroidogenic factor 1 (SF1), dosage-sensitive sex reversal-AHC critical region on the X chromosome gene 1 (DAX1), and serum response factor (SRF): potential mechanism for GnRH pulse frequency regulation of LH beta transcription in the rat. Endocrine 39, 212–219.
| GnRH pulse frequency differentially regulates steroidogenic factor 1 (SF1), dosage-sensitive sex reversal-AHC critical region on the X chromosome gene 1 (DAX1), and serum response factor (SRF): potential mechanism for GnRH pulse frequency regulation of LH beta transcription in the rat.Crossref | GoogleScholarGoogle Scholar | 21409515PubMed |
Carbone, S., Samaniego, Y. A., Cutrera, R., Reynoso, R., Cardoso, N., Scacchi, P., Moguilevsky, J. A., and Ponzo, O. J. (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, 78–84.
| 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).Crossref | GoogleScholarGoogle Scholar | 22178135PubMed |
Ejaredar, M., Nyanza, E. C., Ten, E. K., and Dewey, D. (2015). Phthalate exposure and childrens neurodevelopment: a systematic review. Environ. Res. 142, 51–60.
| Phthalate exposure and childrens neurodevelopment: a systematic review.Crossref | GoogleScholarGoogle Scholar | 26101203PubMed |
Gao, N., Hu, R., Huang, Y., Dao, L., Zhang, C., Liu, Y., Wu, L., Wang, X., Yin, W., Gore, A. C., and Sun, Z. (2018). Specific effects of prenatal DEHP exposure on neuroendocrine gene expression in the developing hypothalamus of male rats. Arch. Toxicol. 92, 501–512.
| Specific effects of prenatal DEHP exposure on neuroendocrine gene expression in the developing hypothalamus of male rats.Crossref | GoogleScholarGoogle Scholar | 28871463PubMed |
Goldman, J. M., Laws, S. C., Balchak, S. K., Cooper, R. L., and Kavlock, R. J. (2000). Endocrine-disrupting chemicals: prepubertal exposures and effects on sexual maturation and thyroid activity in the female rat. A focus on the EDSTAC recommendations. Crit. Rev. Toxicol. 30, 135–196.
| Endocrine-disrupting chemicals: prepubertal exposures and effects on sexual maturation and thyroid activity in the female rat. A focus on the EDSTAC recommendations.Crossref | GoogleScholarGoogle Scholar | 10759430PubMed |
Guo, M., Lai, L., Zong, T., Lin, Y., Yang, B., Zhang, L., Li, M., and 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.
| Exposure to di(2-ethylhexyl) phthalate inhibits luteal function via dysregulation of CD31 and prostaglandin F2alpha in pregnant mice.Crossref | GoogleScholarGoogle Scholar | 25888850PubMed |
Han, X., He, Y., Zeng, G., Wang, Y., Sun, W., Liu, J., Sun, Y., and Yu, J. (2017). Intracerebroventricular injection of RFRP-3 delays puberty onset and stimulates growth hormone secretion in female rats. Reprod. Biol. Endocrinol. 15, 35.
| Intracerebroventricular injection of RFRP-3 delays puberty onset and stimulates growth hormone secretion in female rats.Crossref | GoogleScholarGoogle Scholar | 28464910PubMed |
Hannon, P. R., Niermann, S., and Flaws, J. A. (2016). Acute exposure to di(2-ethylhexyl) phthalate in adulthood causes adverse reproductive outcomes later in life and accelerates reproductive aging in female mice. Toxicol. Sci. 150, 97–108.
| Acute exposure to di(2-ethylhexyl) phthalate in adulthood causes adverse reproductive outcomes later in life and accelerates reproductive aging in female mice.Crossref | GoogleScholarGoogle Scholar | 26678702PubMed |
Hu, M. H., Li, X. F., McCausland, B., Li, S. Y., Gresham, R., Kinsey-Jones, J. S., Gardiner, J. V., Sam, A. H., Bloom, S. R., Poston, L., Lightman, S. L., Murphy, K. G., and O’Byrne, K. T. (2015). Relative importance of the arcuate and anteroventral periventricular kisspeptin neurons in control of puberty and reproductive function in female rats. Endocrinology 156, 2619–2631.
| Relative importance of the arcuate and anteroventral periventricular kisspeptin neurons in control of puberty and reproductive function in female rats.Crossref | GoogleScholarGoogle Scholar | 25875299PubMed |
Johns, L. E., Ferguson, K. K., Soldin, O. P., Cantonwine, D. E., Rivera-González, L. O., DelToro, L. V., Calafat, A. M., Ye, X., Alshawabkeh, A. N., Cordero, J. F., and Meeker, J. D. (2015). Urinary phthalate metabolites in relation to maternal serum thyroid and sex hormone levels during pregnancy: a longitudinal analysis. Reprod. Biol. Endocrinol. 13, 4.
| Urinary phthalate metabolites in relation to maternal serum thyroid and sex hormone levels during pregnancy: a longitudinal analysis.Crossref | GoogleScholarGoogle Scholar | 25596636PubMed |
Kalo, D., Hadas, R., Furman, O., Ben-Ari, J., Maor, Y., Patterson, D. G., Tomey, C., and Roth, Z. (2015). Carryover effects of acute DEHP exposure on ovarian function and oocyte developmental competence in lactating cows. PLoS One 10, e0130896.
| Carryover effects of acute DEHP exposure on ovarian function and oocyte developmental competence in lactating cows.Crossref | GoogleScholarGoogle Scholar | 26154164PubMed |
Karabulut, G., and Barlas, N. (2018). Genotoxic, histologic, immunohistochemical, morphometric and hormonal effects of di-(2-ethylhexyl)-phthalate (DEHP) on reproductive systems in pre-pubertal male rats. Toxicol. Res. (Camb.) 7, 859–873.
| Genotoxic, histologic, immunohistochemical, morphometric and hormonal effects of di-(2-ethylhexyl)-phthalate (DEHP) on reproductive systems in pre-pubertal male rats.Crossref | GoogleScholarGoogle Scholar | 30310663PubMed |
Kirk, S. E., Dalkin, A. C., Yasin, M., Haisenleder, D. J., and Marshall, J. C. (1994). Gonadotropin-releasing hormone pulse frequency regulates expression of pituitary follistatin messenger ribonucleic acid: a mechanism for differential gonadotrope function. Endocrinology 135, 876–880.
| Gonadotropin-releasing hormone pulse frequency regulates expression of pituitary follistatin messenger ribonucleic acid: a mechanism for differential gonadotrope function.Crossref | GoogleScholarGoogle Scholar | 8070381PubMed |
Kuohung, W., and Kaiser, U. B. (2006). GPR54 and KiSS-1: role in the regulation of puberty and reproduction. Rev. Endocr. Metab. Disord. 7, 257–263.
| GPR54 and KiSS-1: role in the regulation of puberty and reproduction.Crossref | GoogleScholarGoogle Scholar | 17206526PubMed |
Lai, F. N., Liu, J. C., Li, L., Ma, J. Y., Liu, X. L., Liu, Y. P., Zhang, X. F., Chen, H., De Felici, M., Dyce, P. W., and Shen, W. (2017). Di (2-ethylhexyl) phthalate impairs steroidogenesis in ovarian follicular cells of prepuberal mice. Arch. Toxicol. 91, 1279–1292.
| Di (2-ethylhexyl) phthalate impairs steroidogenesis in ovarian follicular cells of prepuberal mice.Crossref | GoogleScholarGoogle Scholar | 27405655PubMed |
Li, N., Liu, T., Zhou, L., He, J., and Ye, L. (2012). Di-(2-ethylhcxyl) phthalate reduces progesterone levels and induces apoptosis of ovarian granulosa cell in adult female ICR mice. Environ. Toxicol. Pharmacol. 34, 869–875.
| Di-(2-ethylhcxyl) phthalate reduces progesterone levels and induces apoptosis of ovarian granulosa cell in adult female ICR mice.Crossref | GoogleScholarGoogle Scholar | 22986106PubMed |
Lin, H., Ge, R. S., Chen, G. R., Hu, G. X., Dong, L., Lian, Q. Q., Hardy, D. O., Sottas, C. M., Li, X. K., and Hardy, M. P. (2008). Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero. Proc. Natl. Acad. Sci. USA 105, 7218–7222.
| Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero.Crossref | GoogleScholarGoogle Scholar | 18469139PubMed |
Liu, T., Wang, Y., Yang, M., Shao, P., Duan, L., Li, M., Zhu, M., Yang, J., and Jiang, J. (2018). Di-(2-ethylhexyl) phthalate induces precocious puberty in adolescent female rats. Iran. J. Basic Med. Sci. 21, 848–855.
| 30186573PubMed |
Ma, M., Kondo, T., Ban, S., Umemura, T., Kurahashi, N., Takeda, M., and Kishi, R. (2006). Exposure of prepubertal female rats to inhaled di(2-ethylhexyl)phthalate affects the onset of puberty and postpubertal reproductive functions. Toxicol. Sci. 93, 164–171.
| Exposure of prepubertal female rats to inhaled di(2-ethylhexyl)phthalate affects the onset of puberty and postpubertal reproductive functions.Crossref | GoogleScholarGoogle Scholar | 16763069PubMed |
Noriega, N. C., Howdeshell, K. L., Furr, J., Lambright, C. R., Wilson, V. S., and Gray, L. J. (2009). Pubertal administration of DEHP delays puberty, suppresses testosterone production, and inhibits reproductive tract development in male Sprague–Dawley and Long–Evans rats. Toxicol. Sci. 111, 163–178.
| Pubertal administration of DEHP delays puberty, suppresses testosterone production, and inhibits reproductive tract development in male Sprague–Dawley and Long–Evans rats.Crossref | GoogleScholarGoogle Scholar | 19528224PubMed |
Orisaka, M., Tajima, K., Mizutani, T., Miyamoto, K., Tsang, B. K., Fukuda, S., Yoshida, Y., and Kotsuji, F. (2006). Granulosa cells promote differentiation of cortical stromal cells into theca cells in the bovine ovary. Biol. Reprod. 75, 734–740.
| Granulosa cells promote differentiation of cortical stromal cells into theca cells in the bovine ovary.Crossref | GoogleScholarGoogle Scholar | 16914692PubMed |
Padmanabhan, V., and McNeilly, A. S. (2001). Is there an FSH-releasing factor? Reproduction 121, 21–30.
| Is there an FSH-releasing factor?Crossref | GoogleScholarGoogle Scholar | 11226026PubMed |
Piche, C. D., Sauvageau, D., Vanlian, M., Erythropel, H. C., Robaire, B., and Leask, R. L. (2012). Effects of di-(2-ethylhexyl) phthalate and four of its metabolites on steroidogenesis in MA-10 cells. Ecotoxicol. Environ. Saf. 79, 108–115.
| Effects of di-(2-ethylhexyl) phthalate and four of its metabolites on steroidogenesis in MA-10 cells.Crossref | GoogleScholarGoogle Scholar | 22236953PubMed |
Pinilla, L., Aguilar, E., Dieguez, C., Millar, R. P., and Tena-Sempere, M. (2012). Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol. Rev. 92, 1235–1316.
| Kisspeptins and reproduction: physiological roles and regulatory mechanisms.Crossref | GoogleScholarGoogle Scholar | 22811428PubMed |
Pocar, P., Fiandanese, N., Secchi, C., Berrini, A., Fischer, B., Schmidt, J. S., Schaedlich, K., and Borromeo, V. (2012). Exposure to di(2-ethyl-hexyl) phthalate (DEHP) in utero and during lactation causes long-term pituitary-gonadal axis disruption in male and female mouse offspring. Endocrinology 153, 937–948.
| Exposure to di(2-ethyl-hexyl) phthalate (DEHP) in utero and during lactation causes long-term pituitary-gonadal axis disruption in male and female mouse offspring.Crossref | GoogleScholarGoogle Scholar | 22147016PubMed |
Qiao, L., Zheng, L., and Cai, D. (2007). Study on the di-n-butyl phthalate and di-2-ethylhexyl phthalate level of girl serum related with precocious puberty in Shanghai. Wei Sheng Yan Jiu 36, 93–95.
| 17424861PubMed |
Roa, J., Vigo, E., Castellano, J. M., Navarro, V. M., Fernández-Fernández, R., Casanueva, F. F., Dieguez, C., Aguilar, E., Pinilla, L., and Tena-Sempere, M. (2006). Hypothalamic expression of KiSS-1 system and gonadotropin-releasing effects of kisspeptin in different reproductive states of the female rat. Endocrinology 147, 2864–2878.
| Hypothalamic expression of KiSS-1 system and gonadotropin-releasing effects of kisspeptin in different reproductive states of the female rat.Crossref | GoogleScholarGoogle Scholar | 16527840PubMed |
Schmidt, J. S., Schaedlich, K., Fiandanese, N., Pocar, P., and Fischer, B. (2012). Effects of di(2-ethylhexyl) phthalate (DEHP) on female fertility and adipogenesis in C3H/N mice. Environ. Health Perspect. 120, 1123–1129.
| Effects of di(2-ethylhexyl) phthalate (DEHP) on female fertility and adipogenesis in C3H/N mice.Crossref | GoogleScholarGoogle Scholar | 22588786PubMed |
Sun, D., Zhou, L., Wang, S., Liu, T., Zhu, J., Jia, Y., Xu, J., Chen, H., Wang, Q., Xu, F., Zhang, Y., and Ye, L. (2018). Effect of di-(2-ethylhexyl) phthalate on the hypothalamus–pituitary–thyroid axis in adolescent rat. Endocr. J. 65, 261–268.
| Effect of di-(2-ethylhexyl) phthalate on the hypothalamus–pituitary–thyroid axis in adolescent rat.Crossref | GoogleScholarGoogle Scholar | 29225205PubMed |
Svechnikova, I., Svechnikov, K., and 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.
| The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats.Crossref | GoogleScholarGoogle Scholar | 17761899PubMed |
Tena-Sempere, M. (2010). Kisspeptin/GPR54 system as potential target for endocrine disruption of reproductive development and function. Int. J. Androl. 33, 360–368.
| Kisspeptin/GPR54 system as potential target for endocrine disruption of reproductive development and function.Crossref | GoogleScholarGoogle Scholar | 19906185PubMed |
Tena-Sempere, M. (2012). Deciphering puberty: novel partners, novel mechanisms. Eur. J. Endocrinol. 167, 733–747.
| Deciphering puberty: novel partners, novel mechanisms.Crossref | GoogleScholarGoogle Scholar | 22989465PubMed |
Vo, T. T., Jung, E. M., Dang, V. H., Yoo, Y. M., Choi, K. C., Yu, F. H., and Jeung, E. B. (2009). Di-(2 ethylhexyl) phthalate and flutamide alter gene expression in the testis of immature male rats. Reprod. Biol. Endocrinol. 7, 104.
| Di-(2 ethylhexyl) phthalate and flutamide alter gene expression in the testis of immature male rats.Crossref | GoogleScholarGoogle Scholar | 19781091PubMed |
Wang, X., Yang, Y., Zhang, L., Ma, Y., Han, J., Yang, L., and Zhou, B. (2013). Endocrine disruption by di-(2-ethylhexyl)-phthalate in Chinese rare minnow (Gobiocypris rarus). Environ. Toxicol. Chem. 32, 1846–1854.
| Endocrine disruption by di-(2-ethylhexyl)-phthalate in Chinese rare minnow (Gobiocypris rarus).Crossref | GoogleScholarGoogle Scholar | 23625782PubMed |
Wang, X., Chang, F., Bai, Y., Chen, F., Zhang, J., and Chen, L. (2014). Bisphenol A enhances kisspeptin neurons in anteroventral periventricular nucleus of female mice. J. Endocrinol. 221, 201–213.
| Bisphenol A enhances kisspeptin neurons in anteroventral periventricular nucleus of female mice.Crossref | GoogleScholarGoogle Scholar | 24532816PubMed |
Wen, Y., Liu, S. D., Lei, X., Ling, Y. S., Luo, Y., and Liu, Q. (2015). Association of PAEs with precocious puberty in children: a systematic review and meta-analysis. Int. J. Environ. Res. Public Health 12, 15254–15268.
| Association of PAEs with precocious puberty in children: a systematic review and meta-analysis.Crossref | GoogleScholarGoogle Scholar | 26633449PubMed |
Wu, W., Zhou, F., Wang, Y., Ning, Y., Yang, J. Y., and Zhou, Y. K. (2017). Phthalate levels and related factors in children aged 6–12 years. Environ. Pollut. 220, 990–996.
| Phthalate levels and related factors in children aged 6–12 years.Crossref | GoogleScholarGoogle Scholar | 27876227PubMed |
Xu, C., Chen, J. A., Qiu, Z., Zhao, Q., Luo, J., Yang, L., Zeng, H., Huang, Y., Zhang, L., Cao, J., and Shu, W. (2010). Ovotoxicity and PPAR-mediated aromatase downregulation in female Sprague–Dawley rats following combined oral exposure to benzo[a]pyrene and di-(2-ethylhexyl) phthalate. Toxicol. Lett. 199, 323–332.
| Ovotoxicity and PPAR-mediated aromatase downregulation in female Sprague–Dawley rats following combined oral exposure to benzo[a]pyrene and di-(2-ethylhexyl) phthalate.Crossref | GoogleScholarGoogle Scholar | 20920559PubMed |
Yang, R., Wang, Y. M., Zhang, L., Zhao, Z. M., Zhao, J., and Peng, S. Q. (2016). Prepubertal exposure to an oestrogenic mycotoxin zearalenone induces central precocious puberty in immature female rats through the mechanism of premature activation of hypothalamic kisspeptin-GPR54 signaling. Mol. Cell. Endocrinol. 437, 62–74.
| Prepubertal exposure to an oestrogenic mycotoxin zearalenone induces central precocious puberty in immature female rats through the mechanism of premature activation of hypothalamic kisspeptin-GPR54 signaling.Crossref | GoogleScholarGoogle Scholar | 27519634PubMed |
