Characterization of Ion-Exchange Fibers for Controlled Drug Delivery

Increasing attention has been focused on methods that deliver pharmacologically active compounds (e.g. drugs, peptides and proteins) in a controlled fashion, so that constant, sustained, site-specific or pulsatile action can be attained. Ion-exchange resins have been widely studied in medical and pharmaceutical applications, including controlled drug delivery, leading to commercialisation of some resin based formulations. Ion-exchangers provide an efficient means to adjust and control drug delivery, as the electrostatic interactions enable precise control of the ion-exchange process and, thus, a more uniform and accurate control of drug release compared to systems that are based only on physical interactions. Unlike the resins, only few studies have been reported on ion-exchange fibers in drug delivery. However, the ion-exchange fibers have many advantageous properties compared to the conventional ion-exchange resins, such as more efficient compound loading into and release from the ion-exchanger, easier incorporation of drug-sized compounds, enhanced control of the ion-exchange process, better mechanical, chemical and thermal stability, and good formulation properties, which make the fibers attractive materials for controlled drug delivery systems. In this study, the factors affecting the nature and strength of the binding/loading of drug-sized model compounds into the ion-exchange fibers was evaluated comprehensively and, moreover, the controllability of subsequent drug release/delivery from the fibers was assessed by modifying the conditions of external solutions. Also the feasibility of ion-exchange fibers for simultaneous delivery of two drugs in combination was studied by dual loading. Donnan theory and theoretical modelling were applied to gain mechanistic understanding on these factors. The experimental results imply that incorporation of model compounds into the ion-exchange fibers was attained mainly as a result of ionic bonding, with additional contribution of non-specific interactions. Increasing the ion-exchange capacity of the fiber or decreasing the valence of loaded compounds increased the molar loading, while more efficient release of the compounds was observed consistently at conditions where the valence or concentration of the extracting counter-ion was increased. Donnan theory was capable of fully interpreting the ion-exchange equilibria and the theoretical modelling supported precisely the experimental observations. The physico-chemical characteristics (lipophilicity, hydrogen bonding ability) of the model compounds and the framework of the fibrous ion-exchanger influenced the affinity of the drugs towards the fibers and may, thus, affect both drug loading and release. It was concluded that precisely controlled drug delivery may be tailored for each compound, in particularly, by choosing a suitable ion-exchange fiber and optimizing the delivery system to take into account the external conditions, also when delivering two drugs simultaneously.

Experimental studies on new particle formation and ions

Atmospheric aerosol particles have significant climatic effects. Secondary new particle formation is a globally important source of these particles. Currently, the mechanisms of particle formation and the vapours participating in this process are, however, not truly understood. The recently developed Neutral cluster and Air Ion Spectrometer (NAIS) was widely used in field studies of atmospheric particle formation. The NAIS was calibrated and found to be in adequate agreement with the reference instruments. It was concluded that NAIS can be reliably used to measure ions and particles near the sizes where the atmospheric particle formation begins. The main focus of this thesis was to study new particle formation and participation of ions in this process. To attain this objective, particle and ion formation and growth rates were studied in various environments - at several field sites in Europe, in previously rarely studied sites in Antarctica and Siberia and also in an indoor environment. New particle formation was observed at all sites were studied and the observations were used as indicatives of the particle formation mechanisms. Particle size-dependent growth rates and nucleation mode hygroscopic growth factors were examined to obtain information on the particle growth. It was found that the atmospheric ions participate in the initial steps of new particle formation, although their contribution was minor in the boundary layer. The highest atmospheric particle formation rates were observed at the most polluted sites where the role of ions was the least pronounced. Furthermore, the increase of particle growth rate with size suggested that enhancement of the growth by ions was negligible. Participation of organic vapours in the particle growth was supported by laboratory and field observations. It was addressed that secondary new particle formation can also be a significant source of indoor air particles. These results, extending over a wide variety of environments, give support to previous observations and increase understanding on new particle formation on a global scale.

Observations sur les termes culinaires dans deux San-Antonio de Frédéric Dard

Pro gradu-työni aihe on ruokaterminologiaa käsittelevät ranskan puhekielen ja Pariisin slangin lainasanat sekä kirjailija Frédéric Dardin alias San-Antonion (1921-2000) luomat, ruokatermistöön kuuluvat uudissanat ja -sanonnat kahdessa San-Antonio-romaanissa C'est mort et ça ne sait pas sekä Le fil à couper le beurre. Näissä ns. kioskikirjallisuutta edustavissa rikosromaaneissa seikkailee puheenparttaan ruoka-alan termeillä höystävä, "erikoistehtäviä" hoitava komisario ja naistenmies, San-Antonio. Ranskankielisessä arjen kielenkäytössä vilisee ruokaan liittyviä sanoja ja sanontoja muissakin kuin varsinaisissa ruuanvalmistus- ja ateriointiyhteyksissä. Halusin tarkastella, millaisena tämä yleisesti havaitsemani ilmiö todentuu Frédéric Dardin kahdessa romaanissa, jotka olen valinnut aineistokseni. Frédéric Dard käyttää romaaneissaan varsin omaperäistä kieltä: sekä puhekieltä että Pariisin slangia. Korpukseni koostuu romaaneista poimimistani ruoka-alan termistöä sisältävistä esimerkeistä, joita valmiiseen työhön tuli 228 kappaletta. Jaoin kaikki korpuksesta löytämäni ruokatermit kahteen luokkaan sen mukaan, oliko kirjailija lainannut käyttämänsä sanan tai ilmauksen puhekielestä tai Pariisin slangista (lainatermit), vai oliko hän luonut termin tai ilmauksen itse (neologismit). Määrittelin termin tai ilmauksen neologismiksi, jos se ei esiintynyt joko laisinkaan tai ainakaan kirjailijan tarkoittamassa merkityksessä seuraavissa sanakirjoissa: Le Dictionnaire du français argotique, populaire et familier; Le Dictionnaire de l'argot moderne; Le Dictionnaire du français non conventionnel; Le Dictionnaire de l'argot; Le Dictionnaire du français argotique et populaire; L'argot chez les vrais de vrai ja Trésor de la langue française. Varsinainen tutkimus perustuu sanojen ja ilmausten merkitysten selvittämiseen ja analysointiin. Lainatermien analyysillä tarkoitan lainatermien merkitysten selvitystä em. sanakirjojen avulla. Neologismit analysoin tarkemmin käyttäen em. sanakirjoja sekä tukeutuen gastronomisten ja erityisesti kielitieteellisten lähdeteosteni tarjoamiin rakenteellisiin ja semanttisiin muodostustapoihin ja tekemällä niistä tarvittavat yhteenvedot oikean merkityksen selvittämiseksi. Käsittelin aineiston kaikki ruokatermit. Niiden valtavan lukumäärän vuoksi analysoitavien esimerkkien määrää piti rajoittaa niin, että valmiiseen työhön jäi jokaisesta termistä enintään kaksi esimerkkiä kummastakin korpuksen kirjasta eli yhteensä 228 esimerkkiä. Muut esimerkit luetteloin työn lopusta löytyvään liitteeseen. Neologismianalyysissä selvisi, että Frédéric Dard suosi erityisesti semanttisia muodostustapoja eli olemassa olevan merkityksen muuttamista metaforien ja kielikuvien avulla. Dardin rikas terminologia ja hänen humoristiset oivalluksensa ovat osaltaan rikastuttaneet ranskan puhekieltä.Työssäni totean, että Pariisin slangia ja puhekieltä on totuttu pitämään sosiaalisesti sopimattomana, marginaalisten ryhmien kielenä, vaikka sen ilmauksia saattaa nykyisin kuulla jopa akateemikkojen käyttävän, ja ilmauksia on siirtynyt slangi- ja puhekielestä yleiskieleen. Toivon työni edistävän kiinnostusta kielitaidon parantamiseen San-Antonion tyyliin tutustumisen avulla sekä herättävän mielenkiintoa ranskan kielen vivahteikkuuteen ja monimuotoisuuteen muullakin kuin yleiskielen tasolla. Kielessä ei mielestäni voi olla sellaisia osa-alueita, joiden opiskelu ja osaaminen olisi tarpeetonta.

Tiedettä Pohjantähden alla : Pohjoisen tutkimus ja Ruotsin tiedeseurojen suhteet Ranskaan 1700-luvulla

In the eighteenth century, the birth of scientific societies in Europe created a new framework for scientific cooperation. Through a new contextualist study of the contacts between the first scientific societies in Sweden and the most important science academy in Europe at the time, l Académie des Sciences in Paris, this dissertation aims to shed light on the role taken by the Swedish learned men in the new networks. It seeks to show that the academy model was related to a new idea of specialisation in science. In the course of the eighteenth century, it is argued, the study of the northern phenomena and regions offered the Swedes an important field of speciality with regard to their foreign colleagues. Although historical studies have often underlined the economic, practical undertone of eighteenth-century Swedish science, participation in fashionable scientific pursuits had also become an important scene for representation. However, the views prevailing in Europe tied civilisation and learning closely to the sunnier, southern climates, which had lead to the difficulty of portraying Sweden as a learned country. The image of the scientific North, as well as the Swedish strategies to polish the image of the North as a place for science, are analysed as seen from France. While sixteenth-century historians had preferred to put down the effects of the cold and claim a similarity of northern conditions to the others, the scientific exchange between Swedish and French researchers shows a new tendency to underline the difference of the North and its harsh climate. An explanation is sought by analysing how information about northern phenomena was used in France. In the European academies, new empirical methods had lead to a need for direct observations on different phenomena and circumstances. Rather than curiosities or objects for exoticism, the eighteenth-century depictions of the northern periphery tell about an emerging interest in the most extreme, and often most telling, examples of the workings of the invariable laws of nature. Whereas the idea of accumulating knowledge through cooperation was most manifest in joint astronomical projects, the idea of gathering and comparing data from differing places of observation appears also in other fields, from experimental philosophy to natural studies or medicine. The effects of these developments are studied and explained in connection to the Montesquieuan climate theories and the emerging pre-romantic ideas of man and society.

Käsityökohtaamisia muinaisuuden kanssa : Neulalla neulominen eli kinnasneulatekniikka ...muutakin kuin neulakinnas?

The aim of this study was to find out how the technique of knotless netting is perceived by the craftsperson of the twenty first century. In this study the craftspeople are represented by the researcher herself, seven craftspeople and teachers (3) teaching knotless netting as well as their students (21). The main interests of this study are the mental pictures and relationship to knotless netting that craftspeople have in the twenty first century. Points of focus are also the specific characteristics of knotless netting, as well as experimenting with new and different materials. The aim of these experiments has been to find new and unusual uses for knotless netting. Preserving knotless netting as a craft and technique are also questions dealt with in this study. The methodology of this study is a qualitative and phenomenographic study of several cases. The data collected are interviews of the teachers, observations in two knotless netting courses, questionnaires answered by the students in these courses and experimental samples made by the author and evaluated by other craftspeople. These samples were made during the years 2005-2008. The interviews, questionnaires and evaluations were conducted under winter and spring 2008. The reference literature is comprised from publications in several different fields. In this study ethnography is the most dominant field of reference due to the fact that knotless netting is so strongly linked to history and antiquity. In the past the technique of knotless netting has been passed down from generation to generation in whatever form the teacher has known. There are many different ways of stitching and binding in knotless netting. This technique is closely connected to traditional knotless netting mittens even today. Nowadays knotless knitting is taught in craft schools, evening classes and in other recreational courses. The concrete understanding of knotless netting by means of two-dimensional instructions is challenging. Craftspeople often require somebody to actually demonstrate the correct way to make the stitches and hold the work before they can proceed with the technique. The way knotless netting is perceived by craftspeople is linked to their backgrounds and preconstructed mental images concerning the technique. An etnographer approaches knotless netting in a different way from a crafts-scientist or a person in an evening class wishing to master the technique. The attitude of the teacher is passed on to students and also affects the way the student perceives knotless netting and its possibilities as a technique. A craftsperson has mixed feelings toward knotted netting. On the other hand the surfaces produced by this rare technique are intriguing but the costs due to the slow manufacturing process are seen as an encumbrance.

Xanthine oxidoreductase in essential hypertension and metabolic syndrome : Experimental studies on rodent models

Hypertension, obesity, dyslipidemia and dysglycemia constitute metabolic syndrome, a major public health concern, which is associated with cardiovascular mortality. High dietary salt (NaCl) is the most important dietary risk factor for elevated blood pressure. The kidney has a major role in salt-sensitive hypertension and is vulnerable to harmful effects of increased blood pressure. Elevated serum urate is a common finding in these disorders. While dysregulation of urate excretion is associated with cardiovascular diseases, present studies aimed to clarify the role of xanthine oxidoreductase (XOR), i.e. xanthine dehydrogenase (XDH) and its post-translational isoform xanthine oxidase (XO), in cardiovascular diseases. XOR yields urate from hypoxanthine and xanthine. Low oxygen levels upregulate XOR in addition to other factors. In present studies higher renal XOR activity was found in hypertension-prone rats than in the controls. Furthermore, NaCl intake increased renal XOR dose-dependently. To clarify whether XOR has any causal role in hypertension, rats were kept on NaCl diets for different periods of time, with or without a XOR inhibitor, allopurinol. While allopurinol did not alleviate hypertension, it prevented left ventricular and renal hypertrophy. Nitric oxide synthases (NOS) produce nitric oxide (NO), which mediates vasodilatation. A paucity of NO, produced by NOS inhibition, aggravated hypertension and induced renal XOR, whereas NO generating drug, alleviated salt-induced hypertension without changes in renal XOR. Zucker fa/fa rat is an animal model of metabolic syndrome. These rats developed substantial obesity and modest hypertension and showed increased hepatic and renal XOR activities. XOR was modified by diet and antihypertensive treatment. Cyclosporine (CsA) is a fungal peptide and one of the first-line immunosuppressive drugs used in the management of organ transplantation. Nephrotoxicity ensue high doses resulting in hypertension and limit CsA use. CsA increased renal XO substantially in salt-sensitive rats on a high NaCl diet, indicating a possible role for this reactive oxygen species generating isoform in CsA nephrotoxicity. Renal hypoxia, common to these rodent models of hypertension and obesity, is one of the plausible XOR inducing factors. Although XOR inhibition did not prevent hypertension, present experimental data indicate that XOR plays a role in the pathology of salt-induced cardiac and renal hypertrophy.

Effects of oral calcium sensitizers on experimental heart failure

Suun kautta annosteltava kalsiumherkistäjä parantaa sydämen vajaatoimintaan liittyvää pumppausvajetta kokeellisissa sydämen vajaatoimintamalleissa Huolimatta viime vuosikymmenien lääketieteellisestä kehityksestä krooninen sydämen vajaatoiminta on silti edelleen vakava, elämänlaatua voimakkaasti rajoittava sairaus. Kalsiumherkistäjät ovat uusi, sydämen pumppausvoimaa lisäävä lääkeryhmä. Levosimendaani, kotimaista alkuperää oleva kalsiumherkistäjä, on kliinisessä käytössä akuutin vajaatoiminnan hoitoon suonensisäisesti ja lyhytaikaisesti annosteltavana valmisteena. Levosimendaanilla on aktiivinen metaboliitti, OR-1896, jonka oletetaan olevan vuorokauden mittaisen levosimendaani-infuusion jälkeen havaittujen useita päiviä kestävien hyödyllisisten vaikutuksisten takana. Levosimendaanin kroonisen, suun kautta tapahtuvan annostelun vaikutuksista tieto on vähäisempää, mutta sillä näyttää olevan positiivisia vaikutuksia potilaiden raportoimana. FM Marjut Louhelainen on selvittänyt väitöskirjassaan suun kautta annosteltavan levosimendaanin ja sen pitkäkestoisen aktiivisen metaboliitin vaikutuksia kroonisen vajaatoiminnan hoidossa käyttämällä sekä hypertensiivisen sydäntaudin että 2 tyypin diabeteksen komplisoimaan sydäninfarktin kokeellisia malleja. Tutkimuksessa selvitettiin lisäksi vajaatoimintaan johtavia molekyylitason tapahtumia sydänlihaksessa. Tutkimuksessa osoitettiin, että krooninen suun kautta annosteltu hoito sekä kalsiumherkistäjä levosimendaanilla että sen aktiivisella metaboliitilla estää hypertensiiviseen sydämen vajaatoiminnan aikaasaamaa sydämen uudelleenmuovaantumista ja siihen liittyvää kuolleisuutta. Nämä vaikutukset välittyivät vähentyneen sydänlihassoluhypertrofian, solukuolleisuuden ja neurohumaraalisen aktivaation kautta. Levosimendaanin ja OR-1896:n osoitettiin myös parantavan sydämen pumppausfunktiota tyyppi 2 diabeteksen komplisoimassa sydäninfarktissa. Ei-diabeettiseen tilanteeseen verrattuna diabetekseen liittyvä infarktin jälkeinen vajaatoiminnan kehitys oli yhteydessä lisääntyneeseen tulehdukseen, fibroosiin, solukuolemaan, neurohumoraaliseen aktivaatioon ja ennenaikaiseen kudoksen vanhenemiseen. Sekä levosimendaani, että OR-1869 vähensivät tulehduksen, fibroosin ja solukuoleman merkkejä ja vaimensi neurohumoraalista aktivaatiota. OR-1896 myös vähensi solujen vanhenemiseen liittyvien merkkiaineiden ilmentymistä. Väitöskirjassa todettiin, että suun kautta annosteltuna sekä levosimendaani, että sen aktiivinen metaboliitti OR-1896, omaavat terapeuttista potentiaalia sekä hypertensiivisen sydäntaudin hoitoon että sydäninfarktin jälkeisen vajaatoiminnan estoon. FM Marjut Louhelaisen farmakologian alaan kuuluva väitöskirja Effects of oral calcium sensitizers on experimental heart failure tarkastetaan Helsingin yliopiston Lääketieteellisessä tiedekunnassa perjantaina 29.01.2010 klo 12 (Biomedicum Helsinki, luentosali 2, Haartmaninkatu 8, Helsinki). Vastaväittäjänä toimii professori Raimo Tuominen, Helsingin yliopiston Farmasian tiedekunnasta ja kustoksena professori Eero Mervaala Helsingin yliopiston Lääketieteellisestä tiedekunnasta.

Experimental and computational studies on lipoprotein lipolysis at acidic pH

Atherosclerosis is a disease of the arteries; its characteristic features include chronic inflammation, extra- and intracellular lipid accumulation, extracellular matrix remodeling, and an increase in extracellular matrix volume. The underlying mechanisms in the pathogenesis of advanced atherosclerotic plaques, that involve local acidity of the extracellular fluid, are still incompletely understood. In this thesis project, my co-workers and I studied the different mechanisms by which local extracellular acidity could promote accumulation of the atherogenic apolipoprotein B-100 (apoB-100)-containing plasma lipoprotein particles in the inner layer of the arterial wall, the intima. We found that lipolysis of atherogenic apoB-100-containing plasma lipoprotein particles (LDL, IDL, and sVLDL) by the secretory phospholipase A2 group V (sPLA2-V) enzyme, was increased at acidic pH. Also, the binding of apoB-100-containing plasma lipoprotein particles to human aortic proteoglycans was dramatically enhanced at acidic pH. Additionally, lipolysis by sPLA2-V enzyme further increased this binding. Using proteoglycan-affinity chromatography, we found that sVLDL lipoprotein particles consist of populations, differing in their affinities toward proteoglycans. These populations also contained different amounts of apolipoprotein E (apoE) and apolipoprotein C-III (apoC-III); the amounts of apoC-III and apoE per particle were highest in the population with the lowest affinity toward proteoglycans. Since PLA2-modification of LDL particles has been shown to change their aggregation behavior, we also studied the effect of acidic pH on the monolayer structure covering lipoprotein particles after PLA2-induced hydrolysis. Using molecular dynamics simulations, we found that, in acidity, the monolayer is more tightly packed laterally; moreover, its spontaneous curvature is negative, suggesting that acidity may promote lipoprotein particles fusion. In addition to extracellular lipid accumulation, the apoB-100-containing plasma lipoprotein particles can be taken up by inflammatory cells, namely macrophages. Using radiolabeled lipoprotein particles and cell cultures, we showed that sPLA2-V-modification of LDL, IDL, and sVLDL lipoproteins particles, at neutral or acidic pH, increased their uptake by human monocyte-derived macrophages.

Expression and function of angiotensins in the regulation of intraocular pressure - an experimental study

Glaucoma is a multifactorial long-term ocular neuropathy associated with progressive loss of the visual field, retinal nerve fiber structural abnormalities and optic disc changes. Like arterial hypertension it is usually a symptomless disease, but if left untreated leads to visual disability and eventual blindness. All therapies currently used aim to lower intraocular pressure (IOP) in order to minimize cell death. Drugs with new mechanisms of action could protect glaucomatous eyes against blindness. Renin-angiotensin system (RAS) is known to regulate systemic blood pressure and compounds acting on it are in wide clinical use in the treatment of hypertension and heart failure but not yet in ophthalmological use. There are only few previous studies concerning intraocular RAS, though evidence is accumulating that drugs antagonizing RAS can also lower IOP, the only treatable risk factor in glaucoma. The main aim of this experimental study was to clarify the expression of the renin-angiotensin system in the eye tissues and to test its potential oculohypotensive effects and mechanisms. In addition, the possible relationship between the development of hypertension and IOP was evaluated in animal models. In conclusion, a novel angiotensin receptor type (Mas), as well as ACE2 enzyme- producing agonists for Mas, were described for the first time in the eye structures participating in the regulation of IOP. In addition, a Mas receptor agonist significantly reduced even normal IOP. The effect was abolished by a specific receptor antagonist. Intraocular, local RAS would thus to be involved in the regulation of IOP, probably even more in pathological conditions such as glaucoma though there was no unambiguous relationship between arterial and ocular hypertension. The findings suggest the potential as antiglaucomatous drugs of agents which increase ACE2 activity and the formation of angiotensin (1-7), or activate Mas receptors.

Dietary elecrolytes and cyclosporine toxicity. Experimental studies in spontaneuosly hypertensive rats

Cyclosporine-A (CsA) is widely used after organ transplantation to prevent rejection and in the treatment of autoimmune diseases. Hypertension and nephrotoxicity are common side-effects of CsA. Studies in patients on the prevention of the side-effects of CsA are difficult to conduct because the patients often receive a combination of different drugs thus making study of the side-effects of a single drug impossible. A challenge in experimental studies has been the lack of an animal model in which the side-effects concomitantly occur. Epidemiological data show an association between sodium (Na) intake and blood pressure. There is also evidence on low dietary intake of magnesium (Mg) and potassium (K) and high blood pressure. Our study was designed to develop an experimental model to study the side-effects of CsA in spontaneously hypertensive rats (SHR). On high dietary sodium, CsA caused hypertension, left ventricular hypertrophy (LVH), narrowing of the coronary arteries, small myocardial infarctions, and proteinuria, reduced creatinine clearance and histopathological renal injury in SHR. Loss of Mg into the urine caused by CsA resulted in Mg depletion in the tissues. Renal excretion of dopamine was reduced and the renin-angiotensin-aldosterone system was activated. We investigated the effects of dietary Mg and/or K and the calcium antagonist drug, isradipine, on the prevention of CsA toxicity. Dietary supplementation of Mg alone or in combination with K prevented from the deleterious pathophysiological and histopathological changes in the kidneys and the heart. K alone had little effect. Isradipine protected better than Mg from LVH, but the combination of isradipine and Mg was the most effective. Isradipine did not, however, protect against Mg loss. In our animal model, the combination of high dietary Na and treatment with CsA accelerated the development of the cardiovascular and renal changes clinically known as the side-effects of CsA. Dietary supplementation of Mg and K and reduction of Na intake and the calcium antagonist drug isradipine prevent from the deleterious effects of CsA.

Toxicity of dioxin to developing teeth and salivary glands : An experimental study

Dioxins are ubiquitous environmental poisons having unequivocal adverse health effects on various species. The majority of their effects are thought to be mediated by the aryl hydrocarbon receptor (AhR). Developing human teeth may be sensitive to dioxins and the most toxic dioxin congener, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is developmentally toxic to rodent teeth. Mechanisms of TCDD toxicity can be studied only experimentally. The aim of the present thesis work was to delineate morphological end points of developmental toxicity of TCDD in rat and mouse teeth and salivary glands in vivo and in vitro and to characterize their cellular and molecular background. Mouse embryonic teeth and submandibular gland explants were grown in organ culture without/with TCDD at various concentrations, examined stereomicroscopically and processed for histological examination. The effects of TCDD on cellular mechanisms essential for organogenesis were investigated. The expression of various genes eliciting the response to TCDD exposure or involved in tooth and salivary gland development was studied at the mRNA and/or protein levels by in situ hybridization and immunohistochemistry. Association of the dental effects of TCDD with the resistance of a rat strain to TCDD acute lethality was analyzed in two lactationally exposed rat strains. The effect of TCDD on rat molar tooth mineralization was studied in tissue sections. TCDD dose- and developmental stage-dependently interfered with tooth formation. TCDD prevented early mouse molar tooth morphogenesis and altered cuspal morphology by enhancing programmend cell death, or apoptosis, in dental epithelial cells programmed to undergo apotosis. Cell proliferation was not affected. TCDD impaired mineralization of rat molar dental matrices, possibly by specifically reducing the expression of the mineralization-related dentin sialophosphoprotein gene shown in cultured mouse teeth. The impaired mineralization of rat teeth was accompanied by decreased expression of AhR and the TCDD-inducible xenobiotic-metabolozing enzyme P4501 A1 (CYP1A1), suggesting mediation of the TCDD effect by the AhR pathway. The severe interference by TCDD with rat incisor formation was independent of the genotypic variation of AhR determining the resistance of a rat strain to TCDD acute lethality. The impairment by TCDD of mouse submandibular gland branching morphogenesis was associated with CYP1A1 induction and involved blockage of EGF receptor signalling. In conclusion, TCDD exposure is likely to have activated the AhR pathway in target organs with the consequent activation of other signalling pathways involving developmentally regulated genes. The resultant phenotype is organ specific and modified by epithelial-mesenchymal interactions and dependent on dose as well as the stage of organogenesis at the time of TCDD exposure. Teeth appear to be responsive to TCDD exposure throughout their development.