Inorganic UV-filters in use today often occur as nanoparticles and have a photocatalytic effect, which can be a problem since they can cause negative health effects. This is why Upsalite®, a mesoporous magnesium carbonate recently has been investigated as a UV-filter. Upsalite® itself is however not suitable as a UV-filter since it mainly protects in the UVC range and hence it needs to be complemented by other substances. The substance studied to functionalize Upsalite® in this thesis is titanium dioxide which is an inorganic UV-filter commonly used in sunscreens. In this work two different sol-gel synthesis routes of titanium dioxide have been investigated as well as a co-synthesis of Upsalite® and titanium dioxide. In the first synthesis route already synthesized Upsalite® was mixed with titanium tetra-isopropoxide and 1-propanol. The second synthesis route was a modified version of synthesis routes described in literature where methanol solvent was used and the pressure was altered by CO2. This route was explored due to its resemblance with the Upsalite® synthesis. Pressure, temperature and amount of water were varied to optimize incorporation of Upsalite® and investigate possibilities for a co-synthesis. Subsequently a co-synthesis of Upsalite® and titanium dioxide was performed that resulted in two amorphous composite materials depending on if water was added in the drying procedure or not. When mixing Upsalite® in the synthesis liquid of titanium dioxide, titanium dioxide seems to be deposited on Upsalite®. It is however difficult to determine whether the pores of Upsalite® have been completely filled or if they have collapsed. The acid catalyst HCl promotes formation to crystalline titanium dioxide but Upsalite® instead prevents it. The limited crystallization of titanium dioxide when synthesized with Upsalite® may be due to confinement in the Upsalite® pores. The UV-blocking properties of the TiO2-Upsalite® without HCl are good with an sun protection factor (SPF) of 27 for a 10 wt% blend in a lotion and an SPF of 7 for the sample with HCl. The modified synthesis route of TiO2 showed that it is possible to perform a sol-gel synthesis with a considerably lower amount of water than found in literature and that alteration of temperature and pressure during the synthesis does not affect the crystallization temperature noteworthy. The materials obtained from the co-synthesis are slightly porous, probably consisting of one or several magnesium titanium oxides and a carbonate phase and showed a transmission cutoff in between Upsalite® and titanium dioxide corresponding to an SPF of 5.

L’objet de cette thèse est la synthèse et la caractérisation de nouveaux filtres UV inorganiques nanostructurés, efficaces dans le domaine des UVA. Dans ce contexte, nous avons choisi d’étudier le dioxyde de cérium (CeO2) et l’hématite (α-Fe2O3) en raison notamment de leurs propriétés optiques d’absorption des UV. Deux méthodes de synthèse ont été sélectionnées pour l’élaboration de ces oxydes, purs ou dopés, sous la forme de poudre nanométrique: la co-précipitation et le spray-pyrolyse. Les conditions optimales de synthèse ont été déterminées grâce à de la diffraction des rayons X et de l’analyse thermique. La structure cristalline ainsi que la granulométrie des échantillons obtenus ont été caractérisées par diffraction des rayons X et microscopies électroniques. La granulométrie et la morphologie des échantillons sont reliées aux méthodes de synthèse, aux conditions opératoires (atmosphère et température de calcination), à la nature et à la concentration des éléments dopants. Les propriétés optiques des échantillons suspendus dans de l’éthanol ont été étudiées par spectroscopie d’absorption UV-visible. Elles sont reliées à la granulométrie des échantillons ainsi qu’à des phénomènes localisés au sein de la maille cristallographique (changements de valence, présence de défauts). Les échantillons à base de CeO2 et α-Fe2O3 ont finalement été incorporés en émulsion solaire, à la place de ZnO, afin de tester leurs performances anti-solaires (SPF et FP-UVA) par mesure in vitro. Les résultats montrent que le ZnO peut être positivement remplacé dans les produits de protection solaire par l’oxyde de cérium ou de fer qu’ils soient purs ou dopés. / The subject of this thesis is the synthesis and the characterization of new UVA-efficient nanostructured inorganic UV filters. In this context, we chose to study cerium dioxide (CeO2) and hematite (α-Fe2O3), most importantly because of their optical absorption properties. Two methods were selected to synthesise cerium dioxide and hematite in nanostructured powder form: the co-precipitation method and the spray-pyrolysis method. Cerium dioxide was studied in both non-doped and doped forms. Optimal synthesis conditions were determined by X-ray diffraction and thermal analysis. The crystalline structure and granulometry of the obtained samples were characterised by X-ray diffraction and electronic microscopy techniques. Granulometry and morphology of the samples are linked to: the synthesis method, the experimental conditions (atmosphere and temperature of calcinations), and the nature and concentrations of the dopes. The optical properties of ethanol suspended samples were studied by UV-visible absorption spectroscopy. They are linked to the samples’granulometry as well as localised phenomena in the crystallographic lattice (valence changes, defects presence). Cerium dioxide- and hematite-based samples were finally incorporated in emulsion, instead of ZnO, in order to test their photoprotection performance (SPF and PF-UVA) by measuring in vitro. Results show that ZnO can be positively replaced by pure or doped cerium or iron oxide in sunscreen, when these are associated with the inorganic filter TiO2.

Ziel der vorliegenden Arbeit war die Herstellung, der Einsatz und die Bewertung von Durchfluss-Photoreaktoren für online Prüfungen zur photochemischen Stabilität im HPLC-System (hn- HPLC). Neben der Anfertigung eines für dieses Anforderungsprofil geeigneten Reaktors war es von Interesse, Strahlungsintensitäten zu bestimmen, die Photostabilität von UV-Filtern zu bewerten, sowie analytische Verfahren zu optimieren. Als wichtigste Ergebnisse dieser Arbeit sind: (1) erstmalig aktinometrische Messungen im Durchfluss durchgeführt worden, (2) die eingestrahlten Intensität im Durchfluss-Reaktor mit dem Standard-Sonnenspektrum (COLIPA) verglichen worden, (3) die Bestimmung von 4-Aminobenzoesäure (PABA) und 4-Acetamidobenzoesäure (PAABA) mittels HPLC-hn optimiert und (4) photochemische Umsätze an folgenden UV-Filtern festgestellt worden: 4-Methoxy-zimtsäure-2-ethyl-hexylester, 3-(4'-Methyl)benzyliden-bornan-2-on,1-(4-tert.-Butylphenyl)-3-(4-methoxyphenyl)propan-1.3-dion und 4-Aminobenzoesäure. / The aim of the present thesis was the construction and evaluation of an on-line photochemical reactor for photochemical stability tests in an HPLC-system (hn- HPLC). The work was focused on the production of a functional and effective photochemical reactor, the determination of radiation intensities and the optimisation of analytical methods. Furthermore the stability of UV-filters under exposure to UV-radiation was investigated. The main results of these thesis are presented in the following: (1) the determination of radiation intensities in online photochemical reactors, (2) the comparison of spectra with standard-sun spectra (COLIPA), (3) the optimisation of the determination of 4-aminobenzoic acid (PABA) and 4-acetamidobenzoic acid (PAABA) with an HPLC-hn method (4) the characterisation of photochemical changes of UV-filters: p-methoxy-cinnamic acid-2-ethyl-hexyl ester, 3-(4'-methyl)benzylidene-bornan-2-on,1-(4-tert.-butylphenyl)-3-(4-methoxyphenyl)propan-1,3-dion and p-aminobenzoic acid.

The first objective of this thesis was to investigate effects of endocrine disruptors on the developing brain and gonads of bird embryos. The substances studied were the insecticide methoxychlor, and nine UV-filters (3-benzylidene camphor (3BC), 4 methyl benzylidene camphor (4MBC), benzophenone (BP) 1,2 and 3, 4 hydroxy benzophenone (4 HB), 4 dihydroxy benzophenone (4DHB), benzyl salicylate (BS), and ethyl-4-aminobenzoate Et-PABA)), commonly used in cosmetic products. Some of these substances have no estrogenic effect in vitro, but have been shown to be estrogenic in vivo. The PCB-mixture Clophen A50 is a well-known inducer of biotransformation enzymes and was co-administered with methoxychlor and the UV-filters 3BC and 4MBC. Exposure to 3BC or 4MBC caused ovotestis formation and malformations of the Müllerian ducts in Japanese quail embryos. Co-exposure to one of these compounds and Clophen A50 enhanced the effects, indicating that Clophen A50 potentiates the effects of the UV-filters. Embryonic co-exposure to Clophen A50 and methoxychlor caused a disturbed male sexual behaviour. The metabolites of methoxychlor are estrogen receptor (ER)α-selective, which indicates that the effects on behaviour following embryonic treatment were mediated by ERα. Another objective in this thesis was to localize estrogen receptors (ERs) in the brain of adult and embryonic Japanese quail. The ER localization provides a basis for mechanistic studies on effects of endocrine disruptors, by the identification of estrogen-responsive areas in the brain. We found that ERβ, not previously implicated in sex-differentiation of the brain, was the only ER-subtype present in a sexually dimorphic brain area during differentiation. In conclusion, the estrogenic effects of 3BC, 4MBC and methoxychlor were increased by co-exposure to PCB. These results raise concern since many wildlife species, as well as humans, carry large body burdens of persistent organic pollutants like PCBs, which potentially can interact and enhance the effects of other endocrine disruptors.

Das Schilddrüsenhormon Triiodthyronin (T3) ist ein essenzieller Regulator physiologischer Prozesse der Entwicklung, des Wachstums und im Intermediärstoffwechsel. Täglich werden zahlreiche natürliche und synthetische Stoffe aufgenommen, die mit dem endokrinen System interferieren und deshalb als Endokrine Disruptoren (ED) bezeichnet werden. Zur Untersuchung einer direkten Interferenz von ED mit den Schilddrüsenhormonrezeptoren (TR) und ihrer transkriptionellen Aktivität wurde im Rahmen dieser Arbeit ein neues Luziferase-basiertes T3 Reportergensystem mit TRalpha1-transfizierten humanen Leberzellen aufgebaut. Durch Validierung mit dem synthetischen TR-Agonisten GC-1 und dem Antagonisten NH-3 konnte nachgewiesen werden, dass dieser Assay ein hoch-sensitives System zur Analyse von agonistischen sowie antagonistischen Effekten von Testsubtanzen darstellt. Zur Bestimmung der endokrinen Aktivitäten einiger humanrelevanter Vertreter aus den Stoffkategorien der Nahrungsmittel, Kosmetika, Pestizide und Industriechemikalien wurden Dosis-Wirkungskurven in Aktivierungs- und T3-Kompetitionsexperimenten ermittelt. In mikromolaren Konzentrationen wirkten von insgesamt 21 Testsubstanzen einige als reine Agonisten oder Antagonisten während andere gemischt agonistische/antagonistische Effekte hatten. Aufgrund ihrer hier beobachteten Effekte und der gegebenen Humanexposition wird eine eingehendere Analyse von 4-Methylbenzyliden Campher, 4-Nonylphenol, Acetochlor, Benzophenon 2, Benzophenon 3, Bisphenol A, Genistein, Octylmethoxycinnamat, Tetrabromobisphenol A und Xanthohumol empfohlen. Außerdem erwiesen sich einige Metaboliten von Schilddrüsenhormonen als potente Agonisten im T3-Reportergenassay und bedürfen weiterer Aufmerksamkeit. Für die molekulare Charakterisierung der Einflüsse solcher Substanzen auf die T3-regulierte Transaktivierung konnte mit dem hier etablierten Bioassay ein zuverlässiges neues Testsystem für reproduzierbare Screeningserien geschaffen werden. / Triiodothyronine (T3) is a crucial regulator of many physiological processes during development, growth and metabolism. A variety of natural and synthetic substances, which are collectively termed endocrine disrupters (ED) due to their interference with the endocrine system, is taken up on a daily base. A novel luciferase-based T3-responsive reporter gene system employing a human liver cell line transfected with thyroid hormone receptor (TR) alpha1 was established in this work to elucidate the potential molecular interference of certain ED with TR and their transcriptional activity. This assay was validated to be a highly sensitive and reliable tool for analyzing agonistic and antagonistic effects of test compounds using the synthetic TR agonist GC-1 and the antagonist NH-3. Dose-response data of test compounds contained in food, cosmetics, pesticides, plasticizers and other industrial chemicals were obtained after applying the substances alone in activation assays or in combination with T3 in competition assays. In total 21 test compounds were screened of which some acted as pure agonists or antagonists while others were mixed agonists/antagonists in the micromolar concentration range and only one was without effect. Follow-up studies are recommended for some of these substances with regard to their effects as determined in this bioassay and in light of information known on human exposure, i.e., 4-methylbenzyliden camphor, 4-nonylphenol, acetochlor, benzophenone 2, benzophenone 3, bisphenol A, genistein, octylmethoxycinnamate, tetrabromobisphenol A and xanthohumol. In addition some endogenous metabolites of thyroid hormones were surprisingly potent agonists in the T3 reporter gene assay and merit further attention. The novel bioassay established here represents a reliable tool for the screening and molecular characterization of substances interfering with T3-mediated transactivation of gene expression.

A necessidade de proteger a pele contra os raios ultravioleta (UV) é imprescindível, tendo em vista os efeitos deletérios gerados pelos mesmos. Compostos convencionais com atividade fotoprotetora sofrem interações, instabilidade e em sua maioria protegem contra os raios UVB. Poucos compostos apresentam proteção contra os raios UVA. No ambiente marinho, como nas algas marinhas, adversidades do ambiente relacionadas, principalmente, a exposição solar, aumentam as defesas naturais contra os raios UV por meio da produção de metabólitos secundários que podem absorver/refletir os raios solares, ou agir como antioxidantes. Tais moléculas podem ser produzidas pelas próprias algas ou pelos fungos endofíticos associados a elas. Assim, o presente estudo tem como objetivo investigar o potencial fotoprotetor de extratos, frações e substâncias isoladas dos fungos endofíticos Xylaria sp e Annulohypoxylon stygium, associados à alga vermelha Bostrychia radicans. Bem como de quatro espécies de algas da Antártica, Palmaria decipiens, Monostroma hariotii, Desmarestia anceps e a Gigartina skottsbergii. As algas da Antártica foram disponibilizadas pelo grupo do Prof. Dr. Pio Colepicolo Neto do IQ-USP e o cultivo dos fungos, a extração e o isolamento foram desenvolvidos em parceria com o Laboratório de Química Orgânica do Ambiente Marinho - NPPNS da FCFRP-USP. Os extratos e frações obtidos foram submetidos à análise dos espectros de absorção no UV e à fotodegradação. A seguir, os extratos e frações mais promissoras foram submetidos à avaliação da fototoxicidade em cultura de fibroblastos 3T3 para a determinação da viabilidade celular na presença e ausência da radiação, de acordo com o protocolo OECD TG 432. O fungo A. stygium apresentou frações com absorção no UVB, duas subfrações se mostraram não cito/fototóxicas e são provenientes de frações fotoestáveis. Destas subfrações, duas substâncias, ambas inéditas, foram isoladas e elucidadas por RMN H1, 1D, 2D, IV, ESI, e estas foram consideradas potenciais ativos para fotoproteção no UVB. O fungo Xylaria sp apresentou frações com absorção na região do UV, porém apenas uma, com absorção no UVB se mostrou fotoestável. Esta mesma fração foi considerada cito e fototóxica. Não foi possível identificar as duas substâncias isoladas pela baixa massa. Entretanto, um metabólito já isolado dessa linhagem anteriormente, o ácido gentísico, foi considerado não fototóxico, devendo ser melhor investigado quanto ao seu potencial como filtro biológico. Quanto às macroalgas antárticas, três espécies apresentaram absorção no UV. Apesar de a maioria dos extratos terem sido considerados fotoinstáveis, o extrato da alga D. anceps, de maior rendimento, apresentou frações com ampla absorção no UVA/VIS, no entanto elevada citotoxicidade. Desta fração foi isolada e identificada a fucoxantina (RMN H1 1D e 2D, ESI), um carotenoide marinho que apresentou potencial fototóxico no modelo monocamadas, mas não foi considerada citotóxica. Sendo assim, este pode ser considerado um promissor candidato a ativo cosmético, pelas suas propriedades antioxidantes e de filtro biológico, pois devido a sua alta massa molecular, 658.90 g/mol, pode-se inferir baixa permeação nas camadas viáveis da pele e ausência de fototoxicidade in vivo. Nesse sentido, novos estudos em modelo de pele 3D deverão ser realizados a fim de se comprovar a segurança de uso tópico da fucoxantina. As espécies também devem ser investigadas para outras atividades biológicas uma vez que este material pertence a uma região pouco estudada e estas podem apresentar potencial para os mais diversos empregos farmacológicos ou cosméticos. / The need to protect the skin against ultraviolet (UV) radiation is essential, due to the deleterious effects caused by them. Conventional UV-filters undergo chemical interactions, instability and mostly protect against UVB rays. Few compounds have protection against UVA rays. In the marine environment, especially in marine algae, adversities, mainly related to sun exposure, increases the natural defenses against UV radiation through the production of secondary metabolites that can absorb/reflect the UV radiation, or even act as antioxidants. Such molecules may be produced by algae themselves or by the endophytic fungi associated with them. The present study aims to investigate the potential of new sunscreen extracts, fractions and isolated compounds from endophytic fungi Xylaria sp and Annulohypoxylon stygium, associated with red algae Bostrychia radicans, and four species of algae from Antarctica: Palmaria decipiens, Monostroma hariotii, Desmarestia anceps and Gigartina skottsbergii. The algae material from Antarctica were given by the group of Prof. Dr. Pio Colepicolo Neto, IQ-USP, and the fungi cultivation, extractions and the compounds isolation were obtained in partnership with the Laboratory of Organic Chemistry of the Marine Environment - NPPNS of FCFRP-USP. The extracts and fractions obtained were submitted to analysis of the absorption spectra in the UV and to photodegradation. After that, the most promising extracts and fractions were submitted to the assessment of phototoxicity in 3T3 fibroblasts in culture for determination of cell viability in the presence and absence of radiation, in accordance with the OECD TG 432 protocol. The fungus A. stygium showed fractions with UVB absorption, from there were isolated two novel compounds and had the structure elucidated (RMN H1 1D/2D; IV; ESI). These compounds were considered potential ingredients for photoprotection on the UVB range. The fungus Xylaria sp. showed fractions with absorption on the UV, but only one of them, with UVB absorption, was considered photostable. The same fraction was also considered cyto/ phototoxic. It was not possible identify two of the compounds isolated due its low weight. Therefore, the gentisic acid, a metabolite already isolated from this fungus, was not considered phototoxic, what suggests that it should be better investigated as a potential biological UV filter. Regarding the seaweeds, three species have shown absorption in UV region. Most of the extracts were considered photounstable, but the D. anceps extract, of highest yield, showed fractions with large UVA/VIS absorption, but higher cytotoxic potential. Fucoxanthin, a marine carotenoid, was isolated from this fraction and identified by NMR H1 1D/2D, ESI. This compound showed phototoxic potential in a monolayer model, but it was not considered cytotoxic. Therefore, fucoxanthin is a promising candidate to a cosmetic ingredient, once it has antioxidant and biological UV filter properties and its high molecular weight, 658.90 g/mol, suggests low skin permeation into viable epidermis and absence of in vivo phototoxicity. Thus, more studies using 3D skin model should be performed in order to prove the safety of the fucoxanthin topical use. The species should be also investigated for other biological activities once this material belongs to a poorly studied region and can show potential for many of the pharmacological/cosmetics activities.

La désinfection de l’eau de piscine est essentielle pour prévenir la propagation de maladies infectieuses. Cependant, les désinfectants réagissent avec les composés organiques présents dans l’eau y compris ceux introduits par les baigneurs, tels que les fluides corporels et les crèmes solaires, conduisant à la formation de sous-produits de désinfection (SPD) associés à des effets néfastes sur la santé. Le devenir des filtres UV organiques, présents dans les crèmes solaires et les produits de soins personnels, dans les piscines d'eau de mer chlorées est peu connu. Les objectifs de la présente étude étaient d'étudier la réactivité des filtres UV organiques dans l'eau de mer chlorée, d’identifier les SPD générées par les filtres UV, d'analyser l’occurrence des SPD dans les piscines d'eau de mer, et d'examiner leur génotoxicité. Des expériences de chloration ont été menées dans l'eau de mer reconstituée sur cinq filtres UV couramment utilisés : l’oxybenzone (OXY), le dioxybenzone (DIOXY), l’avobenzone (AVO), l’octyl méthoxycinnamate (OMC), et l’octocrylène (OC). Tous les composés étudiés sauf l’OC ont été dégradés conduisant à la formation de SPD bromés pour lesquels des schémas réactionnels ont été proposés. L'occurrence de ces SPD a été étudiée dans les piscines d'eau de mer où des SPD bromés ont été quantifiés. La génotoxicité de l’hydrate de bromal (BH), l’un des SPD généré par OXY et DIOXY et détecté dans les piscines d'eau de mer, a été évaluée. BH a induit une activité génotoxique dans le test d'Ames et l'essai de comète. Cette étude montre que les filtres UV peuvent agir comme précurseurs pour la formation de SPD génotoxiques dans l’eau de mer chlorée. / Disinfection of swimming pool water is critical to prevent outbreaks of infectious diseases. However, disinfectants react with organic compounds present in water, including anthropogenic inputs (e.g. body fluids, sunscreens), leading to the formation of disinfection byproducts (DBPs) that have been linked to adverse health effects. Little is known about the fate of organic UV filters, present in sunscreens and personal care products, when introduced into chlorinated seawater swimming pools. The aims of the present study were to investigate the reactivity of five commonly used organic UV filters in chlorinated seawater, identify DBPs generated from the UV filters, analyze the occurrence of these DBPs in seawater swimming pools, and examine their genotoxicity. Chlorination experiments were conducted to analyze the reactivity of the UV filters oxybenzone (OXY), dioxybenzone (DIOXY), avobenzone (AVO), octyl methoxycinnamate (OMC), and octocrylene (OC) in reconstituted seawater. All the studied UV filters except OC were degraded in chlorinated seawater resulting in the formation of brominated DBPs. Based on the identified byproducts, transformation pathways were proposed. The occurrence of the identified DBPs was investigated in seawater pools. Several brominated DBPs were identified in seawater pool samples. The genotoxicity of bromal hydrate (BH), which was generated by the benzophenone UV filters OXY and DIOXY and detected in the investigated seawater pools, was assessed. BH induced genotoxic activity in the Ames test and in the comet assay. Overall, this study shows that UV filters can act as precursors for the formation of genotoxic DBPs in chlorinated seawater pools.

Coral bleaching causes the disappearance of unique ecosystems supporting thousands of different species. The corals health depends on its relationship with its endosymbiont, the zooxanthellate Symbiodiniaceae. This mutualistic relationship can be disrupted by anthropogenic chemical pollution by inducing physiologically stress in Symbiodiniaceae. This thesis investigates the effects of organic ultraviolet filter chemical in Symbiodiniaceae of four genera (Fugacium, Effrenium, Symbiodinium, Breviolum), with regards to their growth and photophysiological performance. Six Symbiodiniaceae strains were exposed to a mixture of the most commonly observed UV-filter at five different concentrations. The cells growth during exposure was followed with spectrophotometry optical density measures and flow cytometry cell counts. The photophysiological performance of Symbiodiniaceae cells in presence of UV-filter chemicals was obtained using chlorophyll fluorometry. This experiment revealed strain-specific sensitivity to UV-filter chemicals, where Symbiodiniaceae strains 421 and 4013 showed highest sensitivity on cell growth. A difference in photophysical performance of Symbiodiniaceae exposed to UV-filter chemicals was observed. The ecotoxicological effects observed in Symbiodiniaceae from UV-filter chemical exposure could indicate a contribution to the disruption of the mutualistic relationship between the coral host and Symbiodiniaceae.

Endokrin aktive Substanzen (EACs) sind exogene Substanzen natürlichen oder synthetischen Ursprungs, die mit der Feedbackregulation hormoneller Netzwerke interferieren können und somit deren Homöostase beeinflussen. Störungen der Hypothalamus-Hypophysen-Schilddrüsenachse (HPT-Achse) haben weitreichende Konsequenzen, da Schilddrüsenhormone essentiell für die Regulation von Entwicklung, Wachstum und Stoffwechsel sind. In der vorliegenden Arbeit wurde das Wirkprofil potenter Inhibitoren der thyreotropen Achse am Beispiel von 4-Methylbenzyliden-campher (4-MBC) und Genistein (GEN) untersucht. Der UV-Filter 4-MBC wurde in der ovariektomierten Ratte als goitrogene Substanz identifiziert. 4-MBC interferiert auf Ebene von Hypothalamus und Hypophyse mit der Expression Feedback-assoziierter Gene und beeinflusst daher die Feedbackregulation der thyreotropen Achse. Darüber hinaus wird die Biosynthese von Schilddrüsenhormonen durch Inhibition des Iodidtransports bei gleichzeitig erhöhter messenger RNA (mRNA)-Konzentration des Natrium-Iodid-Symporters (NIS) durch 4-MBC beeinträchtigt. Parallel dazu lässt die verstärkte Expression des Angiogenesemarkers vascular endothelial growth factor (VEGF) nach subakuter Exposition auf die Entstehung einer Hypothyreose schließen. Die damit einhergehenden Veränderungen sind auch in peripheren Organen durch die Analyse 3,3‘,5-Triiod-L-thyronin (T3)-regulierter Zielgene dokumentiert. Zudem wurden diese Effekte maßgeblich durch die Expositionszeit beeinflusst, da nach chronischer Exposition vermutlich auch kompensatorische Prozesse eine wichtige Rolle spielen. Die gezeigten speziesspezifischen Effekte lassen sich möglicherweise auf Unterschiede in der Pharmakokinetik zurückführen, z.B. in Folge differentieller Expression von Cytochrom P450-Genen. / Endocrine active compounds (EACs) can be of natural or synthetic origin and show hormone-like effects that interfere with feedback regulation of hormonal networks. Interferences with the hypothalamic-pituitary-thyroid axis (HPT-axis) result in extensive consequences as thyroid hormones are essential for regulation of development, growth, and metabolism. In the work presented here, the active profile of potent inhibitors of the HPT-axis namely 4-methylbenzylidene-camphor (4-MBC) and genistein (GEN) was investigated. 4-MBC, a UV filter used in sunscreens and various cosmetics, was identified as a goiter causing agent using ovariectomized rats. 4-MBC acts at the level of hypothalamus and pituitary gland by modulating the expression of thyrotropin-releasing hormone (TRH) as well as thyroid-stimulating hormone (TSH) that regulate feedback on the HPT-axis. Furthermore, biosynthesis of thyroid hormones was impaired by 4-MBC secondary to the inhibition of iodide transport with concomitantly increased messenger RNA (mRNA)-levels of the sodium-iodide symporter (NIS). In parallel expression of the angiogenesis marker vascular endothelial growth factor (VEGF) was increased, indicating hypothyroidism. After the application of 4-MBC the expression of L-3,3’,5-triiodothyronine (T3)-regulated target genes was reduced in the periphery both on the mRNA and protein level. The documented species-specific effects indicate a difference in pharmacokinetics, possibly secondary to differential expression of cytochrome P450 genes. GEN is contained in soy and red clover and its mechanistic analysis was carried out in thyroid hormone receptor (TR) deficient mice (TRα0/0). The gender-dependent effects of GEN on tissue specificity did not follow an obvious pattern and warrant continuative analysis. The work presented here supports the assumption that EACs can interfere with function and regulation of the HPT-axis at levels that were previously considered safe.

L’objectif de cette thèse est de développer un concept inédit permettant l’utilisation de silices mésoporeuses pour encapsuler des principes actifs cosmétiques de façon permanente, ce qui permet d’améliorer leur tolérance cutanée, d’optimiser leur stabilité à la lumière tout en préservant leur efficacité et de faciliter leur formulation au sein de produits cosmétiques. Pour cela, la voie consistant à encapsuler des filtres UV à usage cosmétique au sein de silices mésoporeuses de type MCM-41 de façon in-situ a été choisie car elle semblait la plus propice à l’encapsulation d’une grande quantité de principes actifs de façon permanente. Deux filtres UV ont été étudiés un lipophile, nommé Parsol MCX, et un hydrophile, appelé Parsol HS. Pour l’ensemble des principes actifs étudiés, un taux d’encapsulation approprié a été obtenu et les caractérisations, effectuées notamment par RMN du solide, ont permis de montrer que l’encapsulation est effective au sein des pores ce qui, couplé à la bonne stabilité de l’encapsulation dans le cas de l’actifs hydrophile, garantit un contact minimum entre l’actif et la peau du consommateur. En revanche, un relargage important de filtre UV lipophile a été constaté. Il a été établi que les propriétés physico-chimiques des matériaux diffèrent significativement suivant que les principes actifs encapsulés soient lipophiles ou hydrophiles. Dans tous les cas, l’organisation poreuse, l’ordre structural et la morphologie des particules contenant des principes actifs varient significativement par rapport aux silices mésoporeuses de référence de type MCM-41, synthétisées sans principe actif. La présence de principe actif au sein du milieu réactionnel a donc une influence sur la structure et la texture des matériaux obtenus, ce qui est dû aux interactions entre les molécules de principe actif, les espèces silicate et les molécules de tensioactif au sein du milieu réactionnel. / The objective of this thesis is to develop a new concept that consists to permanently encapsulate cosmetic active ingredients into mesoporous silica. The encapsulation of these active molecules improves their skin tolerance, optimizes their light stability while preserving their effectiveness and facilitates their formulation in cosmetic products. Thus, UV filters have been encapsulated in MCM-41 type mesoporous silica by using in-situ route because it seemed the most efficient route to achieve permanently encapsulation of large quantities of active. Two UV filters have been studied. One is lipophilic (Parsol MCX) and the other is a hydrophilic (Parsol HS). For all the active molecules studied, an appropriate encapsulation rate was obtained and the characterizations, particularly these performed by solid-state NMR, have shown that the encapsulation is effective within the pores which, coupled with the good stability of encapsulation in the case of hydrophilic actives, ensures minimal contact between the active and the consumer's skin. In contrast, a significant release of lipophilic UV filter was found. It was established that the physico-chemical properties of the synthesized materials differ significantly according to the lipophilic or hydrophilic nature of the encapsulated molecules. In all cases, the porous organization, the structural order and the morphology of the particles containing active ingredients vary significantly compared to the reference MCM-41 type mesoporous silica, synthesized without active ingredient. Thus, the presence of the active ingredient in the reaction medium has an influence on the structure and the texture of the synthesized materials, which is due to interactions between the actives molecules, the silicate species and the surfactant molecules in the reaction medium.