Origin of an ancient hormone/receptor couple revealed by resurrection of an ancestral estrogen

Markov, Gabriel V.; Gutierrez-Mazariegos, Juliana; Pitrat, Delphine; Billas, I. M. L.; Bonneton, François; Moras, Dino; Hasserodt, Jens; Lecointre, Guillaume; Laudet, Vincent

doi:10.1126/sciadv.1601778

Cited by 62 publications

(62 citation statements)

References 93 publications

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“…[50-52, 61, 62, 107]. Paraestrol A, which has an aromatic A ring, is synthesized by corals binds to the ancestral SR [65,66].…”

Section: What Was the Ancestral Estrogen?mentioning

confidence: 99%

Steroid receptors and vertebrate evolution

Baker

2019

Molecular and Cellular Endocrinology

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Considering that life on earth evolved about 3.7 billion years ago, vertebrates are young, appearing in the fossil record during the Cambrian explosion about 542 to 515 million years ago. Results from sequence analyses of genomes from bacteria, yeast, plants, invertebrates and vertebrates indicate that receptors for adrenal steroids (aldosterone, cortisol), and sex steroids (estrogen, progesterone, testosterone) also are young, with an estrogen receptor and a 3ketosteroid receptor first appearing in basal chordates (cephalochordates: amphioxus), which are close ancestors of vertebrates. Through gene duplication and divergence of the 3-ketosteroid receptor, receptors that respond to androgens, glucocorticoids, mineralocorticoids and progestins evolved in vertebrates. Thus, an ancestral progesterone receptor and an ancestral corticoid receptor, the common ancestor of the glucocorticoid and mineralocorticoid receptors, evolved in jawless vertebrates (cyclostomes: lampreys, hagfish). This was followed by evolution of an androgen receptor, distinct glucocorticoid and mineralocorticoid receptors and estrogen receptorα and -β in cartilaginous fishes (gnathostomes: sharks). Further evolution of mineralocorticoid signaling occurred with the evolution of aldosterone synthase in lungfish, a forerunner of terrestrial vertebrates. Adrenal and sex steroid receptors are not found in echinoderms: and hemichordates, which are ancestors in the lineage of cephalochordates and vertebrates. The evolution of steroid receptors at key nodes in the evolution of vertebrates argues for an important role for steroid receptors in the evolutionary success of vertebrates, considering that the human genome contains about 22,000 genes, which is not much larger than genomes of invertebrates, such as Caenorhabditis elegans (~18,000 genes) and Drosophila (~14,000 genes).

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“…[50-52, 61, 62, 107]. Paraestrol A, which has an aromatic A ring, is synthesized by corals binds to the ancestral SR [65,66].…”

Section: What Was the Ancestral Estrogen?mentioning

confidence: 99%

Steroid receptors and vertebrate evolution

Baker

2019

Molecular and Cellular Endocrinology

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“…Δ 5 -Androstenediol, 5α-androstanediol, and 27-hydroxycholesterol are physiological estrogens [27,46,50,61,67,80]. Paraestrol A, a cholesterol analog with an aromatic A ring and a C3 phenolic group, has been proposed to be one of a class of cholesterol derivatives that may have been transcriptional activators of the ancestral estrogen receptor [15].…”

Section: Promiscuity In Steroids That Activate the Estrogen Receptormentioning

confidence: 99%

“…The earliest ortholog of mammalian ER is found in amphioxus [4,15,[19][20][21], a marine chordate that diverged from vertebrates more than 520 million years ago. Based on parsimony, we propose that one or both of these C19-containing steroids or a related metabolite were ligands for the early chordate ER, with E2 evolving later as the canonical estrogen [9,16].…”

Section: Figure 5 Chemicals From Plants That Act As Estrogensmentioning

confidence: 99%

“…Paraestrol A is a recently described steroid that resembles cholesterol and with an aromatic A ring (Figure 1). Paraestrol A has been proposed to be an ancestral estrogen [15]. Although this steroid has not been found in mammals, clearly paraestrol A or a metabolite, such as 27-OH-paraestrol A, must be considered as a possible 'first' transcription activator of the ER in amphioxus or another chordate in which the first steroid-activated ER evolved [9,15,19,74].…”

Section: Paraestrol Amentioning

confidence: 99%

“…Of the three steroids with a C19 methyl group, the synthesis of 27-hydroxycholesterol from cholesterol is the most parsimonious [9] ( Figure 6). The recent report by Markov et al [15] of paraestrol A, an aromatized cholesterol derivative, provides another potential ancestral ligand for the ER.…”

Section: What Was the Ancestral Estrogen?mentioning

confidence: 99%

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The promiscuous estrogen receptor: evolution of physiological estrogens and response to phytochemicals and endocrine disruptors

Baker¹,

Lathe²

2017

Preprint

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Many actions of estradiol (E2), the principal physiological estrogen in vertebrates, are mediated by estrogen receptor-α (ERα) and ERβ. An important physiological feature of vertebrate ERs is their promiscuous response to several physiological steroids, including estradiol (E2), Δ 5 -androstenediol, 5α-androstanediol, and 27-hydroxycholesterol. A novel structural characteristic of Δ 5 -androstenediol, 5α-androstanediol, and 27-hydroxycholesterol is the presence of a C19 methyl group, which precludes the presence of an aromatic A ring with a C3 phenolic group that is a defining property of E2. The structural diversity of these estrogens can explain the response of the ER to synthetic chemicals such as bisphenol A and DDT, which disrupt estrogen physiology in vertebrates, and the estrogenic activity of a variety of plant-derived chemicals such as genistein, coumestrol, and resveratrol. Diversity in the A ring of physiological estrogens also expands potential structures of industrial chemicals that can act as endocrine disruptors. Compared to E2, synthesis of 27-hydroxycholesterol and Δ 5 -androstenediol is simpler, leading us, based on parsimony, to propose that one or both of these steroids or a related metabolite was a physiological estrogen early in the evolution of the ER, with E2 assuming this role later as the canonical estrogen.In addition to the well-studied role of the ER in reproductive physiology, the ER also is an important transcription factor in non-reproductive tissues such as the cardiovascular system, kidney, bone, and brain.

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Antineoplastic Agents: Environmental Prevalence and Adverse Outcomes in Aquatic Organisms

Wormington

María

Kurita

et al. 2020

Enviro Toxic and Chemistry

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Cancer is the second leading cause of death worldwide, with 9.6 million cancer‐related deaths in 2018. Cancer incidence has increased over time, and so has the prescription rate of chemotherapeutic drugs. These pharmaceuticals, known as antineoplastic agents, enter the aquatic environment via human excretion and wastewater. The objectives of the present critical review were to investigate the risk of antineoplastics to aquatic species and to summarize the current state of knowledge regarding their levels in the environment, because many antineoplastics are not adequately removed during wastewater treatment. We conducted 2 separate literature reviews to synthesize data on the global environmental prevalence and toxicity of antineoplastics. The antineoplastics most frequently detected in the environment included cyclophosphamide, ifosfamide, tamoxifen, methotrexate, and 5‐fluorouracil; all were detectable in multiple water sources, including effluent and surface waters. These antineoplastics span 3 different mechanistic classes, with cyclophosphamide and ifosfamide classified as alkylating agents, tamoxifen as a hormonal agent, and methotrexate and 5‐fluorouracil as antimetabolites. Studies that characterize the risk of antineoplastics released into aquatic environments are scarce. We summarize the biological impacts of the most environmentally prevalent antineoplastics on aquatic organisms and propose an adverse outcome pathway for cyclophosphamide and ifosfamide, 2 widely prescribed drugs with a similar immunotoxic mode of action. Acute and chronic ecotoxicity studies using aquatic models are needed for risk characterization of antineoplastics. Environ Toxicol Chem 2020;39:967–985. © 2020 SETAC

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Origin of an ancient hormone/receptor couple revealed by resurrection of an ancestral estrogen

Abstract: Cladistic analysis allows inference of the structure of an ancestral steroid that acts as a ligand for the ancestral receptor.

Cited by 62 publications

References 93 publications

Steroid receptors and vertebrate evolution

Steroid receptors and vertebrate evolution

The promiscuous estrogen receptor: evolution of physiological estrogens and response to phytochemicals and endocrine disruptors

Antineoplastic Agents: Environmental Prevalence and Adverse Outcomes in Aquatic Organisms

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