Ovarian follicular fluid levels of phthalates and benzophenones in relation to fertility outcomes.

Background: Many endocrine disrupting chemicals (EDCs), for instance phthalates and benzophenones, are associated with adverse fertility outcomes and semen quality parameters.

Objective: To evaluate if concentrations of selected phthalate metabolites and benzophenones measured in follicular fluid are associated with fertility outcomes (i.e.

Xenobiotic Exposure and Migraine-Associated Signaling: A Multimethod Experimental Study Exploring Cellular Assays in Combination with and Mouse Models.

Background: Mechanisms for how environmental chemicals might influence pain has received little attention. Epidemiological studies suggest that environmental factors such as pollutants might play a role in migraine prevalence. Potential targets for pollutants are the transient receptor potential (TRP) channels ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), which on activation release pain-inducing neuropeptide calcitonin gene-related peptide (CGRP).

Lupeol and pristimerin do not inhibit activation of the human sperm CatSper Ca(2+)-channel.

Opposing findings have been published on the regulation of the sperm-specific Ca channel CatSper (cation channel of sperm) in human sperm cells by the plant triterpenoids lupeol and pristimerin. While the original study on this topic found these triterpenoids to act as potent inhibitors of human CatSper, subsequent studies have failed to replicate such an inhibitory effect. It has been suggested that these issues could in part be due to purity issues and/or batch variation between the plant-derived extracts of lupeol and pristimerin obtained for the studies.

In vitro investigation of endocrine disrupting effects of pesticides on Ca-signaling in human sperm cells through actions on the sperm-specific and steroid-activated CatSper Ca-channel.

Background: Ca-signaling controls sperm cell functions necessary for successful fertilization. Multiple endocrine disrupting chemicals have been found to interfere with normal Ca-signaling in human sperm cells through an activation of the sperm-specific CatSper Ca-channel, which is vital for normal male fertility.

Objectives: We investigated 53 pesticides for their ability to interfere with CatSper mediated Ca-signaling and function in human sperm cells.

Human sperm cells can form paracetamol metabolite AM404 that directly interferes with sperm calcium signalling and function through a CatSper-dependent mechanism.

Study Question: Do paracetamol (N-acetyl-para-aminophenol (APAP) or acetaminophen) and/or its metabolites affect human sperm Ca2+-signalling and function?

Summary Answer: While APAP itself does not interact with Ca2+-signalling in human sperm, its metabolite N-arachidonoyl phenolamine (AM404), produced via fatty acid amide hydrolase (FAAH), interferes with human sperm Ca2+-signalling and function through a suggested CatSper channel-dependent action.

What Is Known Already: Studies have shown that adult men with high urinary levels of over-the-counter mild analgesic APAP have impaired sperm motility and increased time-to-pregnancy.

Study Design, Size, Duration: This study consists of (i) an in vivo human pharmaceutical APAP exposure experiment to understand to what degree APAP reaches the sperm cells in the seminal fluid; (ii) in vitro calcium imaging and functional experiments in freshly donated human sperm cells to investigate CatSper channel-dependent activation by APAP and its metabolites; and (iii) experiments to understand the in situ capabilities of human sperm cells to form APAP metabolite AM404.

The antidepressant Sertraline inhibits CatSper Ca2+ channels in human sperm.

Study Question: Do selective serotonin reuptake inhibitor (SSRI) antidepressants affect the function of human sperm?

Summary Answer: The SSRI antidepressant Sertraline (e.g. Zoloft) inhibits the sperm-specific Ca2+ channel CatSper and affects human sperm function in vitro.

Finasteride interferes with prostaglandin-induced CatSper signalling in human sperm.

Ca2+ signalling controls human sperm functions necessary for successful fertilization. Multiple endocrine-disrupting chemicals have been found to activate the CatSper Ca2+ channel and thereby interfering with Ca2+ signalling in human sperm. Finasteride is prescribed to men in the fertile age to treat hair loss and its use has been associated with impaired male fertility.

The Calcium-Sensing Receptor Is Essential for Calcium and Bicarbonate Sensitivity in Human Spermatozoa.

Context: The calcium-sensing receptor (CaSR) is essential to maintain a stable calcium concentration in serum. Spermatozoa are exposed to immense changes in concentrations of CaSR ligands such as calcium, magnesium, and spermine during epididymal maturation, in the ejaculate, and in the female reproductive environment. However, the role of CaSR in human spermatozoa is unknown.

Revisiting the action of steroids and triterpenoids on the human sperm Ca2+ channel CatSper.

The sperm-specific Ca2+ channel CatSper (cation channel of sperm) is vital for male fertility. Contradictory findings have been published on the regulation of human CatSper by the endogenous steroids estradiol, testosterone and hydrocortisone, as well as the plant triterpenoids, lupeol and pristimerin. The aim of this study was to elucidate this controversy by investigating the action of these steroids and plant triterpenoids on human CatSper using population-based Ca2+-fluorimetric measurements, the specific CatSper-inhibitor RU1968 and a functional test assessing the CatSper-dependent penetration of human sperm cells into methylcellulose.

Bisphenol A Diglycidyl Ether (BADGE) and Progesterone Do Not Induce Ca Signals in Boar Sperm Cells.

Aim: Exposure of boar sperm cells to Bisphenol A diglycidyl ether (BADGE) has been shown to lead to reproductive failure in sows, however, the mode of action is unknown. As we have recently shown that BADGE can interfere with Ca signaling in human sperm cells through an action on CatSper, and as CatSper has been shown to be expressed in boar sperm cells, we hypothesized that a similar mechanism in the boar sperm cells could be responsible for the reproductive failure.

Methods: Direct effects of BADGE and the endogenous ligand of human CatSper, progesterone, on Ca signaling in human and boar sperm cells were evaluated side-by-side using a Ca fluorimetric assay measuring changes in intracellular Ca.

Influence of FGF23 and Klotho on male reproduction: Systemic vs direct effects.

Currently, no treatment exists to improve semen quality in most infertile men. Here, we demonstrate systemic and direct effects of Fibroblast growth factor 23 (FGF23) and Klotho, which normally regulate vitamin D and mineral homeostasis, on testicular function. Direct effects are plausible because KLOTHO is expressed in both germ cells and spermatozoa and forms with FGFR1 a specific receptor for the bone-derived hormone FGF23.

Bisphenol A Diglycidyl Ether (BADGE) and Bisphenol Analogs, but Not Bisphenol A (BPA), Activate the CatSper Ca Channel in Human Sperm.

Evidence suggests that bisphenol A diglycidyl ether (BADGE), bisphenol A (BPA), and BPA analogs can interfere with human male fertility. However, the effect directly on human sperm function is not known. The CatSper Ca channel in human sperm controls important sperm functions and is necessary for normal male fertility.

Use of outpatient medical care by headache patients in Germany: a population-based cross-sectional study.

Background: Headache sufferers in need of professional health care often do not utilize the care available, and factors influencing headache-specific physician consultation are not yet understood. Objectives of this study are (1) to assess self-reported headache-specific physician consultations and (2) to identify headache-related and sociodemographic predictors.

Methods: Data of a random sample of the general population in Germany aged ≥14 years were analyzed (N = 2461).

UV filters in matched seminal fluid-, urine-, and serum samples from young men.

Recent in vitro studies have shown that some chemical UV filters mimic the effect of progesterone in the activation of the CatSper Ca2 channel in human spermatozoa. However, so far, the extent of exposure of human spermatozoa to chemical UV filters via the presence of these chemicals in seminal fluid has been unknown. Here, we present levels of UV filters measured in human seminal fluid and comparisons to levels measured in concurrently collected urine and serum samples.

Medium-throughput Screening Assays for Assessment of Effects on Ca2+-Signaling and Acrosome Reaction in Human Sperm.

Ca-signaling is essential to normal sperm cell function and male fertility. Similarly, the acrosome reaction is vital for the ability of a human sperm cell to penetrate the zona pellucida and fertilize the egg. It is therefore of great interest to test compounds (e.

Synergistic activation of CatSper Ca2+ channels in human sperm by oviductal ligands and endocrine disrupting chemicals.

Study Question: Does the chemosensory activation of CatSper Ca2+ channels in human sperm give rise to additive, sub-additive or even synergistic actions among agonists?

Summary Answer: We show that oviductal ligands and endocrine disrupting chemicals (EDCs) activate human CatSper highly synergistically.

What Is Known Already: In human sperm, the sperm-specific CatSper channel controls the intracellular Ca2+ concentration and, thereby, several crucial stages toward fertilization. CatSper is activated by oviductal ligands and structurally diverse EDCs.

Viable acrosome-intact human spermatozoa in the ejaculate as a marker of semen quality and fertility status.

Study Question: Is it possible, in an unbiased and clinical relevant way, to determine the number of viable acrosome-intact human spermatozoa in ejaculates and to use this as a measure of fertility chances?

Summary Answer: Image cytometry enables easy and unbiased quantification of viable acrosome-intact spermatozoa and it correlates with semen quality and fertility status.

What Is Known Already: The presence of the acrosome and its ability to respond to physiological inducers (e.g.

EDC IMPACT: Chemical UV filters can affect human sperm function in a progesterone-like manner.

Human sperm cell function must be precisely regulated to achieve natural fertilization. Progesterone released by the cumulus cells surrounding the egg induces a Ca influx into human sperm cells via the CatSper Ca-channel and thereby controls sperm function. Multiple chemical UV filters have been shown to induce a Ca influx through CatSper, thus mimicking the effect of progesterone on Ca signaling.

Selection of High-Quality Spermatozoa May Be Promoted by Activated Vitamin D in the Woman.

Context: The vitamin D receptor (VDR) and enzymes involved in activation (CYP2R1, CYP27B1) and inactivation (CYP24A1) of vitamin D are expressed in ovary, testes, and spermatozoa.

Objective: Determine responsiveness to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] in spermatozoa from normal and infertile men, and identify the site of exposure and how 1,25(OH)2D3 influences sperm function.

Design: Spermatozoa expressing VDR, CYP2R1, CYP27B1, and CYP24A1 were analyzed in normal and infertile men.

Chemical UV Filters Mimic the Effect of Progesterone on Ca Signaling in Human Sperm Cells.

Progesterone released by cumulus cells surrounding the egg induces a Ca influx into human sperm cells via the cationic channel of sperm (CatSper) Ca channel and controls multiple Ca-dependent responses essential for fertilization. We hypothesized that chemical UV filters may mimic the physiological action of progesterone on CatSper, thus affecting Ca signaling in human sperm cells. We examined 29 UV filters allowed in sunscreens in the United States and/or the European Union for their ability to induce Ca signals in human sperm by applying measurements of the intracellular free Ca concentration.

In vitro bioassay investigations of the endocrine disrupting potential of steviol glycosides and their metabolite steviol, components of the natural sweetener Stevia.

The food industry is moving towards the use of natural sweeteners such as those produced by Stevia rebaudiana due to the number of health and safety concerns surrounding artificial sweeteners. Despite the fact that these sweeteners are natural; they cannot be assumed safe. Steviol glycosides have a steroidal structure and therefore may have the potential to act as an endocrine disruptor in the body.

Direct action of endocrine disrupting chemicals on human sperm.

Synthetic endocrine disrupting chemicals (EDCs), omnipresent in food, household, and personal care products, have been implicated in adverse trends in human reproduction, including infertility and increasing demand for assisted reproduction. Here, we study the action of 96 ubiquitous EDCs on human sperm. We show that structurally diverse EDCs activate the sperm-specific CatSper channel and, thereby, evoke an intracellular Ca(2+) increase, a motility response, and acrosomal exocytosis.

Alternative polyadenylation of tumor suppressor genes in small intestinal neuroendocrine tumors.

The tumorigenesis of small intestinal neuroendocrine tumors (SI-NETs) is poorly understood. Recent studies have associated alternative polyadenylation (APA) with proliferation, cell transformation, and cancer. Polyadenylation is the process in which the pre-messenger RNA is cleaved at a polyA site and a polyA tail is added.

Alterations in polyadenylation and its implications for endocrine disease.

Introduction: Polyadenylation is the process in which the pre-mRNA is cleaved at the poly(A) site and a poly(A) tail is added - a process necessary for normal mRNA formation. Genes with multiple poly(A) sites can undergo alternative polyadenylation (APA), producing distinct mRNA isoforms with different 3' untranslated regions (3' UTRs) and in some cases different coding regions. Two thirds of all human genes undergo APA.

[Birt-Hogg-Dubé syndrome].

Birt-Hogg-Dubé (BHD) is a rare autosomal dominant genodermatosis, characterized by cutaneous hamartomas, pulmonary cysts, spontaneous pneumothorax and kidney tumours. BHD is caused by mutation in the gene which codes for folliculin (FLCN). FLCN is part of the mTOR-AMPK signal transduction pathway.