Successful pregnancy requires the establishment of a highly regulated maternal–fetal environment. This is achieved through the harmonious regulation of steroid hormones, which modulate both maternal and fetal physiology, and are critical for pregnancy maintenance. Defects in steroidogenesis and steroid signaling can lead to pregnancy disorders or even fetal loss. The placenta is a multifunctional, transitory organ which develops at the maternal–fetal interface, and supports fetal development through endocrine signaling, the transport of nutrients and gas exchange. The placenta has the ability to adapt to adverse environments, including hormonal variations, trying to support fetal development. However, if placental function is impaired, or its capacity to adapt is exceeded, fetal development will be compromised. The goal of this review is to explore the relevance of androgens and androgen signaling during pregnancy, specifically in placental development and function. Often considered a mere precursor to placental estrogen synthesis, the placenta in fact secretes androgens throughout pregnancy, and not only contains the androgen steroid nuclear receptor, but also non-genomic membrane receptors for androgens, suggesting a role of androgen signaling in placental function. Moreover, a number of pregnancy disorders, including pre-eclampsia, gestational diabetes, intrauterine growth restriction, and polycystic ovarian syndrome, are associated with abnormal androgen levels and androgen signaling. Understanding the role of androgens in the placenta will provide a greater understanding of the pathophysiology of pregnancy disorders associated with androgen elevation and its consequences.

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An 8-month mixed breed dog (from shelter) was evaluated for its abnormal external genital (enlarged os clitoris protruding externally from the vulva) condition. Dog had phenotypic female appearance. Testicular-like tissue was removed via laparoscopy-assisted gonadectomy. Genotype was determined using blood and gonadal tissue (via histology and immunohistochemistry). Dog had XX chromosomes and was negative for SRY (sex-determining region on the Y chromosome) gene.

An 8-month mixed breed dog (from shelter) was evaluated for its abnormal external genital (enlarged os clitoris protruding externallyfrom the vulva) condition. Dog had phenotypic female appearance. Testicular-like tissue was removed via laparoscopy-assistedgonadectomy. Genotype was determined using blood and gonadal tissue (via histology and immunohistochemistry). Doghad XX chromosomes and was negative for SRY (sex-determining region on the Y chromosome) gene.

Histone lysine demethylase 1A is a master regulator of genes necessary for trophoblast cell proliferation. A proper functioning placenta is critical for pregnancy, fetal growth and development and postnatal health. Trophoblast cell proliferation and differentiation is critical for placental development and function. Recently we demonstrated that the histone lysine demethylase KDM1A binds to androgen receptor (AR) in human and sheep trophoblast cells, and targets the same promoter region of vascular endothelial growth factor A (VEGFA), suggesting a role for KDM1A and AR in early placental angiogenesis. The goal of this study was to determine the function of KDM1A during early placental development. We hypothesized that KDM1A regulates genes that are necessary for trophoblast cell proliferation, and early placental development. To this end, both in vitro and in vivo approaches were used in this study. ACH-3P cells (human first trimester trophoblast cells (CT and EVT) fused with the choriocarcinoma cell line AC1-1) were used, and a KDM1A knock out (KO) cell line was generated using CRISPR-Cas 9 based genome editing. KDM1A KO in ACH-3P cells led to significant (P<0.05) reduction in AR and VEGFA. Furthermore, factors important for cell proliferation and trophoblast cell development high mobility group AT-hook 1 (HMGA1), LIN28, and MYC protooncogene (cMYC) were significantly (P<0.05) lower in KDM1A KO ACH-3P cells. Cell proliferation assays revealed a significant (P<0.05) reduction in KDM1A KO ACH-3P cells compared to scramble controls. An in vivo experiment was conducted to demonstrate a role for KDM1A in placental development, using the sheep as a model. Day 9 hatched blastocysts were flushed and infected with a Lenti-CRISPRv2 KDM1A target construct (n=4) to knockout KDM1A specifically in the trophectoderm, or with SC (n=5). Infected embryos were transferred to recipient ewes and embryos were collected at gestational day 16. Data suggests that KDM1A KO in trophoblast cells is necessary for conceptus elongation. Current experiments are ongoing to determine the effects of KDM1A and AR knockdown using shRNA lentiviral target vectors on conceptus elongation and pregnancy. Collectively these results indicate that KDM1A plays a central role in regulating genes necessary for trophoblast cell proliferation. This project was supported by Agriculture and Food Research Initiative Competitive Grant no. 2019-67015-29000 from the USDA National Institute of Food and Agriculture.