The incidence of metabolic disorders like type 2 diabetes and obesity continues to increase. In addition to the well-known contributors to these disorders, such as food intake and sedentary lifestyle, recent research in the exposure science discipline provides evidence that exposure to endocrine-disrupting chemicals like bisphenol A and phthalates via multiple routes (e.g., food, drink, skin contact) also contribute to the increased risk of metabolic disorders. Endocrine-disrupting chemicals (EDCs) can disrupt any aspect of hormone action. It is becoming increasingly clear that EDCs not only affect endocrine function but also adversely affect immune system function. In this review, we focus on human, animal, and in vitro studies that demonstrate EDC exposure induces dysfunction of the immune system, which, in turn, has detrimental effects on metabolic health. These findings highlight how the immune system is emerging as a novel player by which EDCs may mediate their effects on metabolic health. We also discuss studies highlighting mechanisms by which EDCs affect the immune system. Finally, we consider that a better understanding of the immunomodulatory roles of EDCs will provide clues to enhance metabolic function and contribute toward the long-term goal of reducing the burden of environmentally induced diabetes and obesity.
PMID 29145569 29145569 DOI 10.1210/en.2017-00882 10.1210/en.2017-00882
Cite this article
Bansal, A., Henao‐Mejia, J., & Simmons, R. (2018). Immune System: An Emerging Player in Mediating Effects of Endocrine Disruptors on Metabolic Health. Endocrinology, 159(1), 32-45. https://doi.org/10.1210/en.2017-00882
Bansal A, Henao‐Mejia J, Simmons R. Immune System: An Emerging Player in Mediating Effects of Endocrine Disruptors on Metabolic Health. Endocrinology. 2018;159(1):32-45. doi:10.1210/en.2017-00882
Bansal, Amita, et al. "Immune System: An Emerging Player in Mediating Effects of Endocrine Disruptors on Metabolic Health." Endocrinology, vol. 159, no. 1, 2018, pp. 32-45.
During early pregnancy, human endometrial stromal cells differentiate into secretory decidual cells via a process regulated by ovarian steroid hormones. Decidual cells play a crucial role by secreting various factors that support essential events in forming a functional placenta, including uterine angiogenesis and the differentiation and development of trophoblasts. We previously reported that the conditional ablation of the transcription factor runt-related transcription factor 1 (RUNX1) in the mouse uterus leads to subfertility due to insufficient maternal angiogenesis and impaired trophoblast differentiation. In this study, we examined the role of RUNX1 in facilitating communication mechanisms among human decidual cells and other cell types present in the pregnant uterus. We demonstrate that RUNX1 regulates the conserved hypoxia-inducible factor 2 α-RAB27B pathway in primary human endometrial stromal cells (HESCs) during decidualization, which promotes the secretion of extracellular vesicles (EVs) by these cells. Consequently, the depletion of RUNX1 in HESC led to reduced EV secretion. Mass spectrometry identified several cargo proteins in decidual EVs, including angiopoietin-related protein 2 (ANGPTL2) and IGF2, which could regulate angiogenesis or trophoblast differentiation. We found that RUNX1 directly regulates their expression, resulting in partial changes to these cargoes when it is absent. We observed that delivering EVs lacking ANGPTL2 or IGF2 to human endothelial cells significantly decreased the formation of vascular networks compared to introducing control EVs carrying these factors. Furthermore, adding IGF2-depleted EVs to human trophoblast cells inhibited their differentiation into the extravillous trophoblast lineage. These findings collectively highlight the crucial role of decidual RUNX1 in promoting essential cell-cell interactions for angiogenesis and trophoblast differentiation during placenta formation.
Endocrine-disrupting chemicals are known to interfere with normal reproductive function and hormone signaling. Phthalates, bisphenol A, pesticides, and environmental contaminants such as polychlorinated biphenyls and dioxins are known endocrine-disrupting chemicals that have been shown to negatively affect both male and female reproduction. Exposure to these chemicals occurs on a daily basis owing to these compounds being found in plastics, personal care products, and pesticides. Recently, studies have shown that these chemicals may cause transgenerational effects on reproduction in both males and females. This is of concern because exposure to these chemicals prenatally or during adult life can negatively impact the reproductive health of future generations. This mini-review summarizes the endocrine-disrupting chemicals that humans are exposed to on a daily basis and what is known about the transgenerational effects that these chemicals may have on male and female reproduction.
Androgens, although traditionally thought to be male sex steroids, play important roles in female reproduction, both in healthy and pathological states. This mini-review focuses on recent advances in our knowledge of the role of androgens in the ovary. Androgen receptor (AR) is expressed in oocytes, granulosa cells, and theca cells, and is temporally regulated during follicular development. Mouse knockout studies have shown that AR expression in granulosa cells is critical for normal follicular development and subsequent ovulation. In addition, androgens are involved in regulating dynamic changes in ovarian steroidogenesis that are critical for normal cycling. Androgen effects on follicle development have been incorporated into clinical practice in women with diminished ovarian reserve, albeit with limited success in available literature. At the other extreme, androgen excess leads to disordered follicle development and anovulatory infertility known as polycystic ovary syndrome (PCOS), with studies suggesting that theca cell AR may mediate many of these negative effects. Finally, both prenatal and postnatal animal models of androgen excess have been developed and are being used to study the pathophysiology of PCOS both within the ovary and with regard to overall metabolic health. Taken together, current scientific consensus is that a careful balance of androgen activity in the ovary is necessary for reproductive health in women.
1. Endocrinology. 2014 May;155(5):1956-69. 10.1210/en.2013-2081. Epub 2014
Mar 31. Use of a mouse in vitro fertilization model to origins of health and disease hypothesis. Feuer SK(1), Liu X, Donjacour A, Lin W, Simbulan RK, Giritharan G, Piane LD,
Kolahi K, Ameri K, Maltepe E, Rinaudo PF. (1)Department of Obstetrics, Gynecology and Reproductive Sciences (S.K.F., X.L.,
A.D., W.L., R.K.S., G.G., L.D.P., K.K., P.F.R.), (K.A., E.M.), University of California San Francisco, San Francisco, 94143; Nevada Center for Reproductive Medicine (G.G.), Reno, Nevada 89511;
Obstetric and Gynecology Department (L.D.P.), University of Turin, Turin, Italy;
and Oregon Health & Science University (K.K.), Portland, Oregon 97239. The Developmental Origins of Health and alterations to homeostasis during critical periods individuals to adult-onset chronic diseases syndrome. It remains controversial whether preimplantation embryo manipulation,
clinically used to treat patients with infertility, affects long-term growth and metabolism. To address this controversy, assessed the effects of in vitro fertilization (IVF) mice. We demonstrate that IVF and embryo culture, considered optimal for mouse embryo culture, alter postnatal growth trajectory,
fat accumulation, and glucose metabolism in adult mice. profiling in serum and microarray analysis of sensitive tissues (liver, skeletal muscle, and adipose tissue) changes in metabolic homeostasis, characterized by mitochondrial dysfunction. Adopting a candidate approach, thioredoxin-interacting protein (TXNIP), a key molecule cellular nutritional and oxidative states with metabolic response, for preimplantation stress and demonstrate transcriptional TXNIP misregulation in selected adult tissues. Importantly,
dysregulation of TXNIP expression is associated with enrichment for H4
acetylation at the Txnip promoter that persists through adulthood in adipose tissue. Our data preimplantation embryos to environmental disturbance conception by IVF can reprogram metabolic homeostasis through metabolic,
transcriptional, and epigenetic mechanisms with lasting and fitness. This study has wide clinical importance of continued follow-up of IVF-conceived offspring. 10.1210/en.2013-2081
PMC3990843
24684304 [Indexed for MEDLINE]