Neonatal Exposure to Agonists and Antagonists of Sex Steroid Receptors Affects AMH and FSH Plasma Level and Their Receptors Expression in the Adult Pig Ovary.

Katarzyna Knapczyk-Stwora,Malgorzata Duda,Maria Slomczynska,Patrycja Witek,Malgorzata Grzesiak,Marek Koziorowski

doi:10.3390/ani10010012

Katarzyna Knapczyk-Stwora, Malgorzata Duda + Show 4 more

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https://doi.org/10.3390/ani10010012

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Abstract

Simple SummaryThe ovarian development and the establishment of ovarian reserve during fetal and/or neonatal life is critical for future reproductive success. Many environmental chemicals are known to negatively affect development and physiology of human and animal ovaries by interfering with endocrine systems, resulting in aberrant reproductive functions. The present study shows the long-term impact of neonatal exposure to agonists and antagonists of sex steroid receptors on AMH and FSH signalling in the ovary of adult pigs. Our findings suggest alteration in ovarian follicle recruitment from ovarian reserve arising from neonatal disruption of androgen/estrogen signalling induced by environmental endocrine active compounds. Everyday use of many endocrine disruptors is already prohibited after their harmful impacts on normal physiology have become known. Nevertheless, market introduction of new chemicals with potential deleterious influence on reproductive physiology has continued. Our outcomes confirm that a neonatal window plays an essential role in the physiological programming of ovarian function in adult pigs. The influence of environmental chemicals on this critical neonatal window needs to be investigated in order to gain a comprehensive view of deleterious interactions between endocrine disrupting chemicals and ovarian function.In this study piglets were injected with testosterone propionate (TP, an androgen), flutamide (FLU, an antiandrogen), 4-tert-octylphenol (OP, an estrogenic compound), ICI 182,780 (ICI, an antiestrogen) or corn oil (controls) between postnatal days 1 and 10 (N = 5/group). Then plasma anti-Müllerian hormone (AMH) and follicle stimulating hormone (FSH) concentration and the expression of their receptors were examined in the adult pig ovary. TP and FLU decreased plasma AMH and FSH concentration. In preantral follicles, TP resulted in upregulation of AMHR2 and FSHR expression, but decreased AMH protein abundance. FLU upregulated AMHR2 expression, while OP increased FSHR mRNA. In small antral follicles, OP upregulated ACVR1 and BMPR1A expression, while FLU increased BMPR1A mRNA. FLU and ICI resulted in upregulation of AMHR2 expression. TP and FLU upregulated AMH expression, while it was downregulated in response to OP or ICI. Moreover, OP and ICI resulted in downregulation of FSHR expression, while FLU decreased FSHR protein abundance. In conclusion, neonatal exposure to either agonist or antagonist of androgen receptor affected AMH and FSH signalling systems in preantral follicles. In small antral follicles these systems were influenced by compounds with estrogenic, antiestrogenic, and antiandrogenic activity. Consequently, these hormonal agents may cause an accelerated recruitment of primordial follicles and affect the cycling recruitment of small antral follicles in pigs.

Highlights

The major function of ovarian follicle is the creation of microenvironment for the growth and maturation of the oocyte, which in turn is capable of being fertilized
We have demonstrated that neonatal exposure to EACs displaying androgenic/antiandrogenic and/or estrogenic/antiestrogenic activities affected oocyte-derived growth factors signalling system in the adult porcine ovary, indicating that neonatal period is vital for programming of ovarian function in pigs
We have previously demonstrated the downregulation of FSH receptor (FSHR) in preantral follicles of neonatal pigs exposed prenatally to FLU, which confirms a key role of androgens in porcine folliculogenesis at the early stages [12]

Summary

Introduction

The major function of ovarian follicle is the creation of microenvironment for the growth and maturation of the oocyte, which in turn is capable of being fertilized. Ovarian follicle development through primordial, primary, and secondary stages, preantral-early antral follicle transition as well as oocyte release during ovulation is tightly regulated by an orchestrated action intra- and extra-follicular factors, including growth factors, gonadotropins, and steroids [1]. In the ovary of many mammalian species, including pigs, AMH is mainly expressed by granulosa cells of preantral and small antral follicles [2]. AMH is thought to regulate the recruitment rate of primordial follicles into the expanding follicle pool in order to prevent exhaustion of the follicular reserve in ovaries [3]. Molecular mechanisms involved in AMH action requires binding to the transmembrane dimeric serine–threonine kinase receptors comprised of the AMH-specific type II receptor (AMHR2), and one of three type I receptors: BMPR1A, BMPR1B, or ACVR1. Upon binding to AMHR2, the type I receptor is recruited to form a hetero-oligomeric complex of type I and II receptors to initiate downstream signalling through activation of SMAD-1, SMAD-5, and SMAD-8 (for a review see [5])

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