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

Shannon, Maeve; Rehfeld, Anders; Frizzell, Caroline; Livingstone, Christina; McGonagle, Caoimhe; Skakkebæk, Niels E.; Wielogórska, Ewa; Connolly, Lisa

doi:10.1016/j.mce.2016.03.005

Cited by 29 publications

(26 citation statements)

References 31 publications

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“…The study on BPA by Stiefel et al highlights another overlooked concern in relation to leachable compounds and that is their capacity to act as endocrine disruptors. There is a growing investment in the foods and drinks industry and the regulatory bodies around potential endocrine disruptors of which these plastic leachables fall under. It is critical to assess whether such leachables from disposable bioreactors are making their way through the purification process and into the end product and if so, do these compounds and at what concentrations interact with the endocrine system such as in the reported case of Steviol Glycosides decreasing the activity of the progesterone receptor …”

Section: Discussionmentioning

confidence: 99%

“…It is critical to assess whether such leachables from disposable bioreactors are making their way through the purification process and into the end product and if so, do these compounds and at what concentrations interact with the endocrine system such as in the reported case of Steviol Glycosides decreasing the activity of the progesterone receptor. 27…”

Section: Discussionmentioning

confidence: 99%

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Process‐relevant concentrations of the leachable bDtBPP impact negatively on CHO cell production characteristics

Kelly

McSweeney

Coleman

et al. 2016

Biotechnology Progress

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The biopharmaceutical industry has invested considerably in the implementation of single-use disposable bioreactors in place of or in addition to their stainless steel-counterparts. This new wave of construction materials for disposable bioprocess containers encompass a plethora of uncharacterized secondary compounds that, when in contact with the culture media, can leach, contaminating the bioprocess. One such cytotoxic leachable already receiving attention is bis(2,4-di-tert-butylphenyl)-phosphate (bDtBPP), a breakdown product of the secondary antioxidant Irgafos 168 in polyethylene-film based bags. This compound has been demonstrated to inhibit cell growth at concentrations ranging from 0.12 to 0.73 mg/L across an array of cell lines. Here we demonstrate that a further two CHO cell lines exhibit sensitivity to bDtBPP exposure at concentrations lower than that previously reported (0.035-0.1 mg/L). Furthermore, these inhibitory concentrations reflect bDtBPP levels found to leach early into the bioprocess, exposing reactor inoculums to serious risk. Quantitative label-free LC-MS/MS revealed that irrespective of cell line or concentration of bDtBPP, 8 proteins were found to be commonly differentially expressed in response to exposure to the compound highlighting biological processes related to cellular stress. Although the glycoprofile of the recombinant antibody remains primarily unchanged, we demonstrate that this compound when spiked at meaningful concentrations 72 h into culture considerably reduces the maximum cell density achieved. Studies like this reinforce the requirement for the complete characterization of all potential leachable compounds from disposable materials to assess their risk not only to the patient but also to the production pipeline itself. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1547-1558, 2016.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Process‐relevant concentrations of the leachable bDtBPP impact negatively on CHO cell production characteristics

Kelly

McSweeney

Coleman

et al. 2016

Biotechnology Progress

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“…CatSper can be promiscuously activated by various ligands ( 16 ), including multiple EDCs ( 17 , 18 , 19 , 20 , 21 ). Our recent study examined 29 of the 31 chemical UV filters allowed in sunscreens in the EU and/or US for their ability to induce a rise in [Ca 2+ ] i in human sperm cells and showed that 13 chemical UV filters induced a rise in [Ca 2+ ] i in human sperm cells ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

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

Rehfeld

Egeberg

Almstrup

et al. 2018

Endocrine Connections

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Human sperm cell function must be precisely regulated to achieve natural fertilization. Progesterone released by the cumulus cells surrounding the egg induces a Ca2+ influx into human sperm cells via the CatSper Ca2+-channel and thereby controls sperm function. Multiple chemical UV filters have been shown to induce a Ca2+ influx through CatSper, thus mimicking the effect of progesterone on Ca2+ signaling. We hypothesized that these UV filters could also mimic the effect of progesterone on sperm function. We examined 29 UV filters allowed in sunscreens in the US and/or EU for their ability to affect acrosome reaction, penetration, hyperactivation and viability in human sperm cells. We found that, similar to progesterone, the UV filters 4-MBC, 3-BC, Meradimate, Octisalate, BCSA, HMS and OD-PABA induced acrosome reaction and 3-BC increased sperm penetration into a viscous medium. The capacity of the UV filters to induce acrosome reaction and increase sperm penetration was positively associated with the ability of the UV filters to induce a Ca2+ influx. None of the UV filters induced significant changes in the proportion of hyperactivated cells. In conclusion, chemical UV filters that mimic the effect of progesterone on Ca2+ signaling in human sperm cells can similarly mimic the effect of progesterone on acrosome reaction and sperm penetration. Human exposure to these chemical UV filters may impair fertility by interfering with sperm function, e.g. through induction of premature acrosome reaction. Further studies are needed to confirm the results in vivo.

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“…Interestingly, both testosterone and hydrocortisone were found to antagonize the action of progesterone at physiological concentrations, which may explain why elevated levels of these steroids in the female organism adversely affect fertility [34]. Importantly, a range of structurally diverse molecules including environmental pollutants, endocrine disruptors, odorants, and common drugs have been shown to interact with the CatSper and interfere with hyperactivation signaling (Table 1) [30,[35][36][37][38][39][40][41]. These exogenous chemicals desensitize spermatozoa to physiological CatSper agonists and thus may impair their functional competence.…”

Section: Catsper: Unique Ca2+ Channel Of Sperm Flagellummentioning

confidence: 99%

Perfect date—the review of current research into molecular bases of mammalian fertilization

Trebichalská

Holubcová

2020

J Assist Reprod Genet

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Fertilization is a multistep process during which two terminally differentiated haploid cells, an egg and a sperm, combine to produce a totipotent diploid zygote. In the early 1950s, it became possible to fertilize mammalian eggs in vitro and study the sequence of cellular and molecular events leading to embryo development. Despite all the achievements of assisted reproduction in the last four decades, remarkably little is known about the molecular aspects of human conception. Current fertility research in animal models is casting more light on the complexity of the process all our lives start with. This review article provides an update on the investigation of mammalian fertilization and highlights the practical implications of scientific discoveries in the context of human reproduction and reproductive medicine.

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

Cited by 29 publications

References 31 publications

Process‐relevant concentrations of the leachable bDtBPP impact negatively on CHO cell production characteristics

Process‐relevant concentrations of the leachable bDtBPP impact negatively on CHO cell production characteristics

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

Perfect date—the review of current research into molecular bases of mammalian fertilization

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