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Interpreting in vitro developmental toxicity test battery results: The consideration of toxicokinetics

Bosgra, S. (author), Westerhout, J. (author)

In the EU collaborative project ChemScreen an alternative, in vitro assay-based test strategy was developed to screen compounds for reproductive toxicity. A toxicokinetic modeling approach was used to allow quantitative comparison between effective concentrations in the in vitro test battery and observations of developmental toxicity in vivo....

article 2015

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Inflammation and nutritional science for programs/policies and interpretation of research evidence (INSPIRE)

Raiten, D.J. (author), Sakr Ashour, F.A. (author), Ross, A.C. (author), Meydani, S.N. (author), Dawson, H.D. (author), Stephensen, C.B. (author), Brabin, B.J. (author), Suchdev, P.S. (author), van Ommen, B. (author), Ahluwalia, N. (author), Ahmed, T. (author), Allen, L. (author), Beck, M. (author), Blanchard, H. (author), Brindle, E. (author), Brown, K. (author), Calder, P. (author), Checkley, W. (author), Claycombe, K. (author), Coles, C. (author), Esamai, F. (author), Friis, H. (author), Gardner, E. (author), Grinspoon, S. (author), Guerrant, R. (author), Hellerstein, M. (author), Hunt, J. (author), King, J. (author), Klasing, K. (author), Kramer, B. (author), Koski, K. (author), Northrop-Clewes, C. (author), Pfeiffer, C. (author), Prentice, A. (author), Ramirez-Zea, M. (author), van Rheenan, P. (author), Rink, L. (author), Srinivasa, S. (author), Benn, C.S. (author), Stephensen, C. (author), Suchdev, P. (author), Sullivan, K. (author), Thurnham, D. (author), Varadhan, R. (author), Van Der Ven, A. (author), Walston, J. (author), Xia, J. (author)

An increasing recognition has emerged of the complexities of the global health agenda-specifically, the collision of infections and noncommunicable diseases and the dual burden of over- and undernutrition. Of particular practical concern are both 1) the need for a better understanding of the bidirectional relations between nutritional status and...

article 2015

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Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling

Louisse, J. (author), Bosgra, S. (author), Blaauboer, B.J. (author), Rietjens, I.M.C.M. (author), Verwei, M. (author)

The use of laboratory animals for toxicity testing in chemical safety assessment meets increasing ethical, economic and legislative constraints. The development, validation and application of reliable alternatives for in vivo toxicity testing are therefore urgently needed. In order to use toxicity data obtained from in vitro assays for risk...

article 2015

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Prediction of in vivo developmental toxicity of all‑trans‑retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling

Louisse, J. (author), Bosgra, S. (author), Blaauboer, B.J. (author), Rietjens, Y.M.C.M. (author), Verwei, M. (author)

article 2014

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Decrease of intracellular pH as possible mechanism of embryotoxicity of glycol ether alkoxyacetic acid metabolites

Louisse, J. (author), Bai, Y. (author), Verwei, M. (author), van de Sandt, J.J.M. (author), Blaauboer, B.J. (author), Rietjens, I.M.C.M. (author), TNO Kwaliteit van Leven (author)

Embryotoxicity of glycol ethers is caused by their alkoxyacetic acid metabolites, but the mechanism underlying the embryotoxicity of these acid metabolites is so far not known. The present study investigates a possible mechanism underlying the embryotoxicity of glycol ether alkoxyacetic acid metabolites using the methoxyacetic acid (MAA)...

article 2010

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Xenobiotic metabolism in human skin and 3D human skin reconstructs: A review

Gibbs, S. (author), van de Sandt, J.J.M. (author), Merk, H.F. (author), Lockley, D.J. (author), Pendlington, R.U. (author), Pease, C.K. (author), TNO Kwaliteit van Leven (author)

In this review, we discuss and compare studies of xenobiotic metabolism in both human skin and 3D human skin reconstructs. In comparison to the liver, the skin is a less studied organ in terms of characterising metabolic capability. While the skin forms the major protective barrier to environmental chemical exposure, it is also a potential...

article 2007

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Repeated topical treatment, in contrast to single oral doses, with Vitamin A-containing preparations does not affect plasma concentrations of retinol, retinyl esters or retinoic acids in female subjects of child-bearing age

Nohynek, G.J. (author), Meuling, W.J.A. (author), Vaes, W.H.J. (author), Lawrence, R.S. (author), Shapiro, S. (author), Schulte, S. (author), Steiling, W. (author), Bausch, J. (author), Gerber, E. (author), Sasa, H. (author), Nau, H. (author), TNO Kwaliteit van Leven (author)

Background: Vitamin A is widely used in cosmetic preparations. Given that oral Vitamin A and its metabolites present a potential reproductive risk, the present study investigated the effect of topical Vitamin A on human endogenous plasma levels of Vitamin A and its metabolites. Methods: Two groups of 14 female volunteers of child-bearing age...

article 2006

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Prediction of in vivo embryotoxic effect levels with a combination of in vitro studies and PBPK modelling

Verwei, M. (author), van Burgsteden, J.A. (author), Krul, C.A.M. (author), van de Sandt, J.J.M. (author), Freidig, A.P. (author), TNO Kwaliteit van Leven (author)

The new EU legislations for chemicals (Registration, Evaluation and Authorization of Chemicals, REACH) and cosmetics (Seventh Amendment) stimulate the acceptance of in vitro and in silico approaches to test chemicals for their potential to cause reproductive effects. In the current study seven compounds with known in vivo developmental effects...

article 2006

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Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles

Gaubius Instituut TNO (author), Grefhorst, A. (author), Elzinga, B.M. (author), Voshol, P.J. (author), Plösch, T. (author), Kok, T. (author), Bloks, V.W. (author), van der Sluijs, F.H. (author), Havekes, L.M. (author), Romijn, J.A. (author), Verkade, H.J. (author), Kuipers, F. (author)

The oxysterol-activated liver X receptor (LXR) provides a link between sterol and fatty acid metabolism; activation of LXR induces transcription of lipogenic genes. This study shows that induction of the lipogenic genes Srebp-1c, Fas, and Acc1 upon administration of the synthetic LXR agonist T0901317 to C57BL/6J mice (10 mg/kg/day, 4 days) is...

article 2002

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Development of an androgen reporter gene assay (AR-LUX) utilizing a human cell line with an endogenously regulated androgen receptor

Blankvoort, B.M.G. (author), de Groene, E.M. (author), van Meeteren-Kreikamp, A.P. (author), Witkamp, R.F. (author), Rodenburg, R.J.T. (author), Aarts, J.M.M.J.G. (author), Centraal Instituut voor Voedingsonderzoek TNO (author)

The aim of the work described in this report is to develop and characterize a cell-based androgen reporter assay. For this purpose, the androgen receptor (AR) expressing human breast cancer cell line T47D was stably transfected with a luciferase gene under transcriptional control of the PB-ARE-2 androgen response element. The application of this...

article 2001

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Inhibition of apolipoprotein(a) synthesis in cynomolgus monkey hepatocytes by retinoids via involvement of the retinoic acid receptor

Neele, D.M. (author), de Wit, E.C.M. (author), Princen, H.M.G. (author), Gaubius instituut TNO (author)

We have shown previously that retinoids induce apolipoprotein (apo) A-I gene expression in cultured cynomolgus hepatocytes and do not have an effect on apo B-100 synthesis. In the present study, the effect of retinoids on apolipoprotein(a) (apo(a)) synthesis in cultured hepatocytes was investigated. The addition of all-trans retinoic acid (at-RA...

article 1999

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Fibrate-modulated expression of fibrinogen, plasminogen activator inhibitor-1 and apolipoprotein A-I in cultured cynomolgus monkey hepatocytes. Role of the peroxisome proliferator-activated receptor-α

Kockx, M. (author), Princen, H.M.G. (author), Kooistra, T. (author), Gaubius Instituut TNO (author)

Fibrates are used to lower plasma triglycerides and cholesterol levels in hyperlipidemic patients. In addition, fibrates have been found to alter the plasma concentrations of fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and apolipoprotein A-I (apo A-I). We have investigated the in vitro effects of fibrates on fibrinogen, PAI-1 and apo A...

article 1998

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Effect of steroid hormones and retinoids on the formation of capillary-like tubular structures of human microvascular endothelial cells in fibrin matrices is related to urokinase expression

Lansink, M. (author), Koolwijk, P. (author), van Hinsbergh, V. (author), Kooistra, T. (author), Gaubius Instituut TNO (author)

Angiogenesis, the formation of new capillary blood vessels, is a feature of a variety of pathological processes. To study the effects of a specific group of hormones (all ligands of the steroid/retinoid/thyroid hormone receptor superfamily) on the angiogenic process in humans, we have used a model system in which human microvascular endothelial...

article 1998

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Synthesis, storage and regulated secretion of tissue-type plasminogen activator by cultured rat heart endothelial cells

Emeis, J.J. (author), van den Hoogen, C.M. (author), Diglio, C.A. (author), Gaubius Instituut TNO (author)

The synthesis, storage and regulated secretion (acute release) of tissue-type plasminogen activator (tPA) were studied in cultured rat heart endothelial (RHE) cells. In this study, special attention was paid to the correspondence between tPA metabolism in RHE cells in vitro and tPA metabolism in rats in vivo. RHE cells synthetized tPA, as shown...

article 1998

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Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor: Contribution to the hypertriglyceridemic action of retinoids

Gaubius Instituut TNO (author), Vu-Dac, N. (author), Gervois, P. (author), Torra, I.P. (author), Fruchart, J.C. (author), Kosykh, V. (author), Kooistra, T. (author), Princen, H.M.G. (author), Dallongeville, J. (author), Staels, B. (author)

Hypertriglyceridemia is a metabolic complication of retinoid therapy. In this study, we analyzed whether retinoids increase the expression of apo C- III, an antagonist of plasma triglyceride catabolism. In men, isotretinoin treatment (80 mg/d; 5 d) resulted in elevated plasma apo C-III, but not apo E concentrations. In human hepatoma HepG2 cells...

article 1998

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Studies on the mechanism of fibrate-inhibited expression of plasminogen activator inhibitor-1 in cultured hepatocytes from cynomolgus monkey

Arts, J. (author), Kooistra, T. (author), Gaubius Laboratory TNO Preventie en Gezondheid (author)

Fibrates are widely used drugs in hyperlipidemic disorders. In addition to lowering serum triglyceride levels, fibrates have also been shown to reduce elevated plasma plasminogen activator inhibitor-1 (PAI-1) levels in vivo. We demonstrate that fibrates suppress PAI-1 synthesis in cultured cynomolgus monkey hepatocytes in a concentration...

article 1997

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Differences in metabolism and isomerization of all-trans-retinoic acid and 9-cis-retinoic acid between human endothelial cells and hepatocytes

Lansink, M. (author), van Bennekum, A.M. (author), Blaner, W.S. (author), Kooistra, T. (author), TNO Preventie en Gezondheid (author)

Retinoic acid stimulates the expression of tissue-type plasminogen activator (t-PA) in vascular endothelial cells in vitro and enhances t-PA levels in plasma and tissues in vivo. Compared with the in vivo situation, high retinoic acid concentrations are required to induce optimally t-PA expression in vitro. These findings led us to study...

article 1997

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Mechanism of the slow induction of apolipoprotein A-I synthesis by retinoids in cynomolgus hepatocytes: Involvement of retinoic acid and retinoid X receptors

Gaubius Instituut TNO Centraal Instituut voor Voedingsonderzoek TNO TNO Voeding (author), Kaptein, A. (author), Neele, D.M. (author), Twisk, J. (author), Hendriks, H.F.J. (author), Kooistra, T. (author), Princen, H.M.G. (author)

We showed previously that retinoids stimulate apolipoprotein A-I (apoA- I) synthesis in cultured cynomolgus hepatocytes only after a 24-h lag phase. Here we report on the biochemical background of the slow response, the requirement for high retinoic acid concentrations, and the involvement of different retinoid receptors. The time course of the...

article 1997

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Retinoid metabolism and all-trans retinoic acid-induced growth inhibition in head and neck squamous cell carcinoma cell lines

TNO Voeding Centraal Instituut voor Voedingsonderzoek TNO (author), Braakhuis, B.J.M. (author), Klaassen, I. (author), van der Leede, B.M. (author), Cloos, J. (author), Brakenhoff, R.H. (author), Copper, M.P. (author), Teerlink, T. (author), Hendriks, H.F.J. (author), van der Saag, P.T. (author), Snow, G.B. (author)

Retinoids can reverse potentially premalignant lesions and prevent second primary tumours in patients with head and neck squamous cell carcinoma (HNSCC). Furthermore, it has been reported that acquired resistance to all-trans retinoic acid (RA) in leukaemia is associated with decreased plasma peak levels, probably the result of enhanced retinoid...

article 1997

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Retinoid (vitamin A) metabolism: A review

Hendriks, H.F.J. (author), Centraal Instituut voor Voedingsonderzoek TNO (author)

Objective and conclusion: An overview is given of our understanding of the uptake and metabolism of retinoids. The mechanisms underlying retinol uptake by organs and tissues are still unsettled. The retinol-binding proteins CRBP I and CRBP II appear to play an essential role in retinyl ester hydrolysis and formation and in retinoic acid...

article 1996