ECE2016 Oral Communications Reproduction & Endocrine Disruption (5 abstracts)
LHCGR signaling promotes gonadal-like cell differentiation and proliferation in gonadectomy-induced adrenocortical tumorigenesis in mice
Marcin Chrusciel 1, , Milena Doroszko 1 , Meike Jakobi 1 , Michal Brouze 1 , Donata Ponikwicka-Tyszko 3 , Piotr Bernaczyk 4 , Slawomir Anisimowicz 5 , Slawomir Wolczynski 2, , Jorma Toppari 1, , Ilpo Huhtaniemi 1, & Nafis Rahman 1,
1Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; 2Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Biolystok, Poland; 3Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland; 4Department of Pathology, Medical University of Bialystok, Bialystok, Poland; 5Center of Gynecology and Reproductive Endocrinology Artemida, Bialystok, Poland; 6Department of Pediatrics, University of Turku, Turku, Finland; 7Institute of Reproductive and Developmental Biology, Imperial College London, London, UK.
Adrenocortical tumorigenesis in prepubertally gonadectomized (GDX) DBA/2J mice has been attributed to chronically elevated luteinizing hormone (LH) and ectopic expression of luteinizing hormone receptor (LHCGR) and GATA-4 transcription factor. We analyzed now the mechanistic role of LH-LHCGR activation in GDX-induced adrenocortical tumorigenesis in intact and ovariectomized (OVX) wild-type (WT) and Lhcgr-/- mice in the DBA/2J genetic background mice, or by treating OVX DBA/2J mice with gonadotropin-releasing hormone antagonist (GnRH-a, Cetrorelix; 2.3 mg/kg/24 h for 21 days). The adrenal glands of 6 mo-old OVX Lhcgr-/- mice were significantly smaller than their haploinsufficient (Lhcgr+/-) or OVX WT control littermates. Histopathology of OVX Lhcgr-/- adrenals showed lack of gonadal-like sex-steroid producing large lipid-laden cells, termed B cells, whereas non-steroidogenic GATA-4-positive spindle-shaped cells, known as A cells, were observed in both intact and OVX Lhcgr-/- mice. Furthermore, OVX Lhcgr-/- mouse adrenals displayed downregulated gonad-specific markers Foxl2, Spinwl1, Cyp19 and Ers2. Lack of sex steroid producing B cells in Lhcgr-/- adrenals resulted in decreased plasma estradiol and progesterone levels and significantly smaller uterus vs. WT control. GnRH-a treatment of 12 mo-old OVX DBA/2J mice significantly reduced the weight of adrenal glands, followed by the downregulated expression of proliferation marker Mki67, gonad-specific genes Lhcgr, Cyp19, Spinlw1 and GATA-4 co-regulator Zfpm2. Taken together, these data provides evidence for LHCGR signaling promoting the differentiation and proliferation of neoplastic sex steroidogenic B cells in GDX-induced adrenocortical tumorigenesis.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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