Zimmerman Kurt L, Panciera David L, Hoeschele Ina, Monroe W Edward, Todd Stephanie Michelle, Werre Stephen R, LeRoith Tanya, Fecteau Kellie, Lake Bathilda B
Department of Biomedical Sciences and Pathobiology, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States.
Department of Small Animal Clinical Sciences, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States.
Front Vet Sci. 2018 Oct 9;5:231. doi: 10.3389/fvets.2018.00231. eCollection 2018.
Scottish terriers (ST) frequently have increased serum alkaline phosphatase (ALP) of the steroid isoform. Many of these also have high serum concentrations of adrenal sex steroids. The study's objective was to determine the cause of increased sex steroids in ST with increased ALP. Adrenal gland suppression and stimulation were compared by low dose dexamethasone (LDDS), human chorionic gonadotropin (HCG) and adrenocorticotropic hormone (ACTH) response tests. Resting plasma pituitary hormones were measured. Steroidogenesis-related mRNA expression was evaluated in six ST with increased ALP, eight dogs of other breeds with pituitary-dependent hyperadrenocorticism (HAC), and seven normal dogs. The genome-wide association of single nucleotide polymorphisms (SNP) with ALP activity was evaluated in 168 ST. ALP (reference interval 8-70 U/L) was high in all ST (1,054 U/L) and HAC (985 U/L) dogs. All HAC dogs and 2/8 ST had increased cortisol post-ACTH administration. All ST and 2/7 Normal dogs had increased sex steroids post-ACTH. ST and Normal dogs had similar post-challenge adrenal steroid profiles following LDDS and HCG. Surprisingly, mRNA of hydroxysteroid 17-beta dehydrogenase 2 (HSD17B2) was lower in ST and Normal dogs than HAC. HSD17B2 facilities metabolism of sex steroids. A SNP region was identified on chromosome 5 in proximity to HSD17B2 that correlated with increased serum ALP. ST in this study with increased ALP had a normal pituitary-adrenal axis in relationship to glucocorticoids and luteinizing hormone. We speculate the identified SNP and HSD17B2 gene may have a role in the pathogenesis of elevated sex steroids and ALP in ST.
苏格兰梗犬(ST)的血清碱性磷酸酶(ALP)类固醇同工酶水平常常升高。其中许多犬还具有较高的血清肾上腺性类固醇浓度。该研究的目的是确定ALP升高的ST中性类固醇增加的原因。通过低剂量地塞米松(LDDS)、人绒毛膜促性腺激素(HCG)和促肾上腺皮质激素(ACTH)反应试验比较肾上腺抑制和刺激情况。测量静息血浆垂体激素水平。在6只ALP升高的ST、8只患有垂体依赖性肾上腺皮质功能亢进(HAC)的其他品种犬和7只正常犬中评估类固醇生成相关的mRNA表达。在168只ST中评估单核苷酸多态性(SNP)与ALP活性的全基因组关联。所有ST(1054 U/L)和HAC(985 U/L)犬的ALP(参考区间8 - 70 U/L)均较高。所有HAC犬和2/8的ST在给予ACTH后皮质醇升高。所有ST和2/7的正常犬在给予ACTH后性类固醇升高。ST和正常犬在LDDS和HCG刺激后肾上腺类固醇谱相似。令人惊讶的是,ST和正常犬中羟基类固醇17-β脱氢酶2(HSD17B2)的mRNA低于HAC犬。HSD17B2促进性类固醇的代谢。在靠近HSD17B2的5号染色体上鉴定出一个SNP区域,其与血清ALP升高相关。本研究中ALP升高的ST在糖皮质激素和促黄体生成素方面垂体 - 肾上腺轴正常。我们推测所鉴定的SNP和HSD17B2基因可能在ST中性类固醇和ALP升高的发病机制中起作用。