Humans experience ubiquitous exposures to estrogenic environmental chemicals from food, personal care products, and other industrial and consumer goods. Bisphenol A (BPA), a well-studied xenoestrogen, is known to alter development of estrogen-sensitive organs including the brain, reproductive tract, and mammary gland. Bisphenol S (BPS), which has a similar chemical structure to BPA, is also used in many consumer products, but its effects on estrogen-sensitive organs in mammals has not been thoroughly examined. In our study, pregnant CD-1 mice were orally exposed to BPS or ethinyl estradiol (EE2, a positive control for estrogenicity) from gestational day 9 through postnatal day (PND) 2, the period when many estrogen-sensitive organs are developing. After weaning, the offspring were administered either oil (vehicle) or an estrogen challenge (1 μg EE2/kg/day) for ten days starting at PND21 (prior to puberty), PND80 (early adulthood), or PND260 (later adulthood). Timing of puberty was evaluated in females by noting the date on which vaginal opening occurred. After the 10 day estrogen challenge, we evaluated the response of endocrine sensitive organs through measurements of organ weight, tissue morphology, and gene expression in both males and females. We observed dose- and sex-specific effects of BPS and EE2 treatment, as well as alterations in the responses of males and females to the estrogen challenge. This study sheds light on the effects of low dose xenoestrogen exposures on estrogen-sensitive organs including the reproductive tract and mammary gland. Furthermore, it improves our understanding of the influence of environmental chemicals on secular trends of earlier age of puberty in girls reported over the past few decades.

Bisphenol S (BPS) is an industrial chemical used in the process of polymerization of polycarbonate plastics and epoxy resins and thus can be found in various plastic products and thermal papers. The microbiota disrupting effect of BPS on the community structure of the microbiome has already been reported, but little is known on how BPS affects bacterial activity and function. To analyze these effects, we cultivated the simplified human intestinal microbiota (SIHUMIx) in bioreactors at a concentration of 45 µM BPS. By determining biomass, growth of SIHUMIx was followed but no differences during BPS exposure were observed. To validate if the membrane composition was affected, fatty acid methyl esters (FAMEs) profiles were compared. Changes in the individual membrane fatty acid composition could not been described; however, the saturation level of the membranes slightly increased during BPS exposure. By applying targeted metabolomics to quantify short-chain fatty acids (SCFA), it was shown that the activity of SIHUMIx was unaffected. Metaproteomics revealed temporal effect on the community structure and function, showing that BPS has minor effects on the structure or functionality of SIHUMIx.

Background: The light-cured resin-based pit and fissure sealants success and longevity are enhanced by sufficient curing. Multiple emission peak Light Emitting Diode Light Curing Units offer a wider range of wavelengths and different levels of irradiances to ensure sufficient curing.The irradiance is considered a main curing factor that can affect the material properties. Purpose: The aim of this study was to assess the effect of different settings of a multiwave LED LCU on the degree of conversion and microhardness of a pit and fissure sealant comparing the irradiance of 1000 mW/cm2 to 1400 mW/cm2 and 3200 mW/cm2 irradiances of the LCU using manufacturer’s guidelines for curing times at 2, 4 and, 6 mm distances. Methods: A multiwave LED light curing unit was evaluated on three different irradiance levels 1000 mW/cm2 (S), 1400 mW/cm2 (H), and 3200 mW/cm2 (X). A total of 90 samples made from the fissure sealant were fabricated and divided into eighteen groups (n=5/group). Samples were cured following manufacturer’s guidelines of curing times for each curing mode at 2, 4, or 6 mm distance between the light tip and top of samples. The DC was measured using (ATR-FTIR) spectroscopy. The KHN test was performed on five different locations of each specimen using a hardness tester (Leco LM247AT, MI, USA, software; Confident V 2.5.2). Results: The top DC for H-8 was significantly higher than S-10 at 2 and 4mm, H-20 DC was significantly lower than S-30 at only 2mm. The bottom DC for H-8 was significantly higher than S-10 at 2mm only, H-20 DC was significantly lower than S-30 at 4 and 6mm only. H-8 KHN at top surface was significantly lower than S-10 at 2mm only, H-20 was significantly lower than S-30 at 2 and 6mm only. H-8 KHN at bottom surface was significantly lower than S-10 at 4 and 6mm but significantly higher at 2mm. H-20 was significantly lower than S-30 at 2mm but significantly higher at 4 and 6mm. The top DC for X-3 was significantly lower than S-10 at all curing distances with no significant difference at all curing distances between X-9 and S-30. The bottom DC for X-3 was significantly higher than S-10 at all curing distances with no significant difference between X-9 and S-30. X-3 KHN at top surface was significantly lower than S-10s at all curing distances. X-9 was significantly lower than S-30 at 6mm only. X-3 KHN at bottom surface was significantly lower than S-10 at 2 and 4mm only with no significant difference at all curing distances between X-9 and S-30. Conclusions: Using a multiwave LED LCU to polymerize Delton Opaque resin-based fissure sealants will result in an optimal DC and KHN values for any irradiance level if the curing distance is kept at 4 mm or less and with at least two cycles of the shortest curing time recommended by the manufacturer. Using a multiwave LED LCU with 1000, 1400 or 3200 mW/cm2 irradiance levels with shortest curing times recommended resulted in unsatisfactory DC and KHN levels. LED LCU with high and extra high irradiance levels (1400 and 3200 mW/cm2) can result in high DC and KHN levels when used adequately. Xtra Power mode (3200 mW/cm2) used on shortest curing time (3 seconds) resulted in significantly lower mechanical properties and for that reason it is not recommended to be used.

Step-growth polymerization provided an effective method for the preparation of several high performance polymers. Step-growth polymerization was used for syntheses of poly(siloxane imides), polyesters, poly(triazole esters), poly(triazole ether esters), and epoxy networks. Each of these polymeric systems exhibited novel structures, and either photoreactive capabilities, or high performance properties. There is an increasing trend towards the development of photoactive adhesives. In particular these polymers are often used in flip bonding, lithography, stimuli responsive polymers, drug delivery, and reversible adhesives. The ability to tailor polymer properties carefully with exposure to light allows for very unique stimuli responsive properties for many applications. This dissertation primarily investigates photoreactive polymers for reversible adhesion for use in the fabrication of microelectronic devices. In particular cyclobutane diimide functionality within polyimides and poly(siloxane imides) and o-nitro benzyl ester functionality within polyesters acted effectively as chromophores to this end. Thermal solution imidization allowed for the effective synthesis of polyimides and poly(siloxane imides). 1,2,3,4-Cyclobutane tetracarboxylic dianhydride acted as the chromophore within the polymer backbone. The polyimides obtained exhibited dispersibility only in dipolar, aprotic, high boiling solvents such as DMAc or NMP. The obtained poly(siloxane imides) demonstrated enhanced dispersibility in lower boiling organic solvents such as THF and CHCl₃. Dynamic mechanical analysis and tensile testing effectively measure the mechanical properties of the photoactive poly(siloxane imides) and confirmed elastomeric properties. Atomic force microscopy confirmed microphase separation of the photoactive poly(siloxane imides). ¹H NMR spectroscopy confirmed formation of maleimide peaks upon exposure to narrow band UV light with a wavelength of 254 nm. This suggested photo-cleavage of the cyclobutane diimide units within the polymer backbone. Melt transesterification offered a facile method for the synthesis of o-nitro benzyl ester-containing polyesters. ¹H NMR spectroscopy confirmed the structures of the photoactive polyesters and size exclusion chromatography confirmed reasonable molecular weights and polydispersities of the obtained samples. ¹H NMR spectroscopy also demonstrated a decrease in the integration of the resonance corresponding to the o-nitro benzyl ester functionality relative to the photo-stable m-nitro benzyl ester functionality upon exposure to high-intensity UV light, suggesting photo-degradation of the adhesive. ASTM wedge testing verified a decrease in fracture energy of the adhesive upon UV exposure, comparable to the decrease in fracture energy of a commercial hot-melt adhesive upon an increase in temperature. Click chemistry was used to synthesize polyesters and segmented block copolyesters. Triazole-containing homopolyesters exhibited a marked increase (~40 °C) in Tg, relative to structurally analogous classical polyesters synthesized in the melt. However, the triazole-containing homopolyesters exhibited insignificant dispersibility in many organic solvents and melt-pressed films exhibited poor flexibility. Incorporation of azide-functionalized poly(propylene glycol) difunctional oligomers in the synthesis of triazole-containing polyesters resulted in segmented block copolyesters which exhibited enhanced dispersibility and film robustness relative to the triazole-containing homopolyesters. The segmented triazole-containing polyesters all demonstrated a soft segment Tg near -62 °C, indicating microphase separation. Dynamic mechanical analysis confirmed the presence of a rubbery plateau, with increasing plateau moduli as a function of hard segment content, as well as increasing flow temperatures as a function of hard segment content. Tensile testing revealed increasing tensile strength as a function of hard segment, approaching 10 MPa for the 50 wt % HS sample. Atomic force microscopy confirmed the presence of microphase separated domains, as well as semicrystalline domains. These results indicated the effectiveness of click chemistry towards the synthesis of polyesters and segmented block copolyesters. Click chemistry was also used for the synthesis of photoactive polyesters and segmented block polyesters. The preparation of 2-nitro-p-xylylene glycol bispropiolate allowed for the synthesis of triazole-containing polyesters, which exhibited poor dispersibility and flexibility of melt-pressed films. The synthesis of segmented photoactive polyesters afforded photoactive polyesters with improved dispersibility and film robustness. ¹H NMR spectroscopy confirmed the photodegradation of the o-nitro benzyl functional groups within the triazole-containing polyesters, which indicated the potential utility of these polyesters for reversible adhesion. Synthesis of the glycidyl ether of 2,2,4,4-tetramethyl-1,3-cyclobutane diol (CBDOGE) allowed for the subsequent preparation of epoxy networks which did not contain bisphenol-A or bisphenol-A derivatives. Preparation of analogous epoxy networks from the glycidyl ether of bisphenol-A (BPA-GE) provided a method for control experiments. Tensile testing demonstrated that, dependent on network Tg, the epoxy networks prepared from CBDOGE exhibited similar Young's moduli and tensile strain at break as epoxy networks prepared from BPAGE. Dynamic mechanical analysis demonstrated similar glassy moduli for the epoxy networks, regardless of the glycidyl ether utilized. Tg and rubbery plateau moduli varied as a function of diamine molecular weight. Melt rheology demonstrated a gel time of 150 minutes for the preparation of epoxy networks from CBDO-GE and 78 minutes for the preparation of epoxy networks from BPA-GE, with the difference attributed to increased sterics surrounding CBDO-GE. These results indicated the suitability of CBDO-GE as a replacement for BPA-GE in many applications. / Ph. D.

Die weltweit mehr als 7500 Amphibienarten sind durch anthropogene Ursachen wie Habitatzerstörung, Krankheitsverbreitung, Klimawandel und Umweltverschmutzung in ihrem Bestand bedroht. Einige der Ursachen sind kaum erforscht, so die Verschmutzung aquatischer Ökosysteme durch endokrine Disruptoren (EDs), Substanzen, die mit dem Hormonsystem interagieren. Ausgehend von neuen molekularen Markern, welche die Ermittlung des genetischen Geschlechts erstmals bei einigen Hyliden und Bufoniden erlauben, wurde in der vorliegenden Arbeit auf die Wirkung des synthetischen Östrogens 17α- Ethinylestradiol (EE2)und des Weichmachers Bisphenol A (BPA) fokussiert. Für drei Bufonidenarten wurde zunächst die Geschlechtsgebundenheit von Mikrosatelliten getestet und ein XX/XY-System nachgewiesen. Diese und bereits etablierte Marker wurden anschließend in ein neu entwickeltes Versuchsdesign für ED-Studien integriert: Nach gleichzeitiger Aufzucht von Modell- (Xenopus laevis) und Nicht-Modell-Arten (Hyla arborea, Bufo viridis) unter EE2- bzw. BPA- Exposition wurde das genetische Geschlecht bestimmt und mit dem anatomisch und histologisch ermittelten phänotypischen Geschlecht erglichen. Die drei Anuren zeigten starke Empfindlichkeitsunterschiede gegenüber beiden EDs. Umweltrelevante Konzentrationen beeinflussten die somatische Entwicklung und führten zu artspezifischen Gonaden-Fehlbildungen. EE2 bewirkte zahlreiche partielle und komplette Geschlechtsumwandlungen, mit stärkeren Effekten bei X. laevis. Diese Arbeit zeigt somit, dass bereits niedrige EE2- und BPA-Konzentrationen zu starken Schädigungen führen können und die Substanzen aufgrund ihrer erheblichen aquatischen Präsenz als ernstzunehmende Faktoren der Amphibienkrise anzusehen sind. Die Ermittlung des genetischen Geschlechts wird als wichtig eingestuft, um verlässliche Aussagen über ED-Effekte zu treffen. Zudem sollten an der Modell-Art X. laevis gewonnene Erkenntnisse nicht vorbehaltlos auf andere Amphibienarten extrapoliert werden. / The more than 7500 known amphibian species are globally threatened, mainly due to anthropogenic causes like habitat destruction, dispersing diseases, climate change and environmental pollution. Some of the causes are barely investigated, e.g. the pollution of aquatic ecosystems with endocrine disrupting compounds (EDCs), substances that interfere with the hormone system. Based on new molecular markers, for the first time allowing genetic sexing in some hylids and bufonids, this thesis focused on the effects of the synthetic estrogen 7α-ethinylestradiol(EE2) and the plasticizer bisphenol A (BPA). Initially, several microsatellite markers were tested for sex-linkage in three bufonid species, and an XX/XY system could be revealed. Subsequently, these and other established markers were integrated into a newly developed experimental design for EDC-research: after simultaneous exposure of model (Xenopus laevis) and non-model species (Hyla arborea, Bufo viridis) to EE2 or BPA, metamorphs were genetically sexed. Anatomically and histologically determined phenotypic sexes were directly compared with the genetic sex of each individual. The three anurans showed striking differences in their susceptibilities in both EDCexperiments. Environmentally relevant concentrations affected the somatic development and led to species-specific gonadal anomalies. In addition, EE2 provoked high numbers of mixed sex and completely sex-reversed individuals, with more pronounced effects in X. laevis than in the two non-model species. This work shows that low concentrations of EE2 and BPA lead to severe damages. Due to their widespread presence in the aquatic environment, these substances might contribute to the worldwide amphibian crisis. To produce reliable results in EDC-studies, genetic sexing is considered important. Furthermore, findings gained with the model species X. laevis should not unreservedly be extrapolated to other amphibian species.

The search and research for high performance materials for aerospace applications is a continuous evolving process. Among several fibre reinforced polymers, carbon fibre reinforced polymer (CFRP) is well known for its high specific stiffness and strength. Though high modulus and high strength carbon fibre with structural resin systems have currently been established reasonably well and are catering to a wide variety of aerospace structural applications, these properties are generally directional with very high properties along the fibre direction dominated by fibres and low in other directions depending mainly on the resin properties. Thus, there is a need to enhance the mechanical properties of the resin systems for better load transfer and to improve the resin dominated properties like shear strength and properties in directions other than along the fibre. Use of carbon nanotubes (CNTs) with their extraordinary specific stiffness and strength apparently has great potential as an additional reinforcement in resin for development of CNT-CFRP nanocomposites. However, there are several issues that need to be addressed such as compatibility of a particular resin with CNTs, amount of CNTs that can be added, uniform dispersion of these nanotubes, surface treatment and curing process etc., for optimal enhancement of the required properties. Epoxy and cyanate ester resin systems are finding applications in aerospace structures owing to their desirable set of properties. Of these, bisphenol E cyanate ester (BECy) resin of low viscosity with its low moisture absorption, better dimensional stability, and superior mechanical properties can establish itself as potential structural resin system for these applications. BECy in particular has the advantage of being more suitable for out of autoclave manufacturing process such as Vacuum Assisted Resin Transfer Molding (VARTM). Literature shows that, significant work has been carried out by various researchers reporting improvements using CNTs in epoxy resins along with various associated problems. However, studies on effects of addition of CNTs /fCNTs to BECy-CFRP composite system are not well reported. Thus, objective of this work is to study the effects of adding pristine and functionalized CNTs to low viscosity cyanate ester as well as epoxy resin systems. Further, to study the effects on mechanical properties of nanocomposites with carbon fibre reinforcement in these CNT dispersed resin system through a combination of experimental and computational approaches. Multiwall carbon nanotubes (CNTs) without and with different chemical functionalization are chosen to be added to epoxy and BECy resins. The quantity of these CNTs /fCNTs is varied in steps up to 1% by weight. Different methods of mixing such as shear mixing, ultrasonication and combined mixing cycles are implemented to achieve uniform dispersion of these nanotubes in the resin system. Standard test samples are prepared from these mixtures of nanotubes in resin systems to study the variation in mechanical properties. Further, these nanotubes added resin systems are used in fabricating CFRP laminates by VARTM process. Both uni-directional and bi-directional laminates are made with the above modified resin systems with CNTs/fCNTs. Series of experimental investigations are carried out to study various aspects involved in making of nanocomposites and the effects of the same on different mechanical properties of the nanocomposites. Standard specimens are cut out from these laminates to evaluate them for tension, compression, flexure, shear and interlaminar shear strength. The main parameters investigated are the effects of varied quantity of CNTs and functionalized CNTs in the resin mix and in CFRP nanocomposites, effect of different mixing / curing cycles etc. on the mechanical properties of the nanocomposites. The investigations have yielded very interesting and encouraging results to arrive at optimum quantity of CNTs to be added and also the effects of functionalization to achieve enhanced mechanical properties. In addition, correlation of mechanical property enhancements with failure mechanisms, dispersion behaviour and participation of CNTs / fCNTs in load transfer are explained with the aid of scanning electron microscope images. Computational studies are carried out through atomistic models using computational tools to estimate the mechanical properties, understand and validate the effects of various parameters studied through series of experimental investigations. An atomistic model is built taking into consideration the nanoscale effects of the single wall carbon nanotubes (SWCNTs) and its reinforcement in the BECy resin. Using these atomistic models, mechanical properties of individual SWCNT, BECy polymer resin, polymer with different quantities of added SWCNT, and the CFRP laminates with improved resin are computed. As the interaction of CNT with the polymer is only at the outermost layer and the mechanical properties of either MWCNTs or SWCNTs are too high compared to resin systems, it is not expected to have any difference in the final outcome whether it is MWCNT or SWCNT. Hence, only SWCNTs are considered in computational studies as it helps in reducing the complexity of atomistic models and computational time when coupled with polymer resin. This is valid even for functionalized CNT as functionalization is also a surface phenomenon. To start with, the mechanical behaviour of SWCNT is studied using molecular mechanics approach. Molecular mechanics based finite element analysis is adopted to evaluate the mechanical properties of armchair, zigzag and chiral SWCNT of different diameters. Three different types of atomic bonds, i.e., carbon-carbon covalent bond and two types of carbon-carbon van der Waals bonds are considered in the carbon nanotube system. The stiffness values of these bonds are calculated using the molecular potentials, namely Morse potential function and Lennard-Jones interaction potential function respectively and these stiffness values are assigned to spring elements in the finite element model of the SWCNT. The importance of inclusion of Lennard-Jones interactions is highlighted in this study. Effect of these non-bonded interactions is studied by making the numerical stiffness of these bonds to negligible levels and found that they significantly reduce the mechanical properties. The effect of non-bonded Lennard-Jones atomic interactions (van der Waal interactions) considered here is a novelty in this work which has not been considered in previous research works. The finite element model of the SWCNT is constructed, appropriate boundary conditions are applied and the behaviour of mechanical properties of SWCNT is studied. It is found that the longitudinal tensile strength and maximum tensile strain of armchair SWCNTs is greater than that of zigzag and chiral SWCNTs and its value increases with increasing SWCNT diameter. The estimated values of the mechanical properties obtained agree well with the published literature data determined using other techniques. As the systems become more complicated with the inclusion of polymers, molecular dynamics (MD) method using well established codes is more adoptable to study the effect of SWCNTs on BECy. Hence, it is used to model and solve the nanosystems to generate their stress-strain behavior. Further, MD approach followed here can effectively include interfacial interaction between polymer and the CNTs as well. Mechanical properties of SWCNT functionalized SWCNT (fSWCNT), pure BECy resin and that of the CNT nanocomposite consisting of specific quantity of SWCNT / fSWCNT in BECy are estimated using MD method. Atomistic models of SWCNT, fSWCNT, BECy, BECy with specific quantities of CNT / fSWCNT are constructed. A monomer of BECy is modelled and stabilized before its usage as a building block for modelling of BECy resin and to compute its properties. A cell of specific size containing monomers of BECy and another cell of same size with SWCNT at centre surrounded by BECy monomer molecules are built. The appropriate quantity of SWCNT in resin is modelled. This model captures the required density of the composite resin. The models so constructed are subjected to geometric optimization satisfying the convergence criteria and equilibrated through molecular dynamics to obtain a stable structure. The minimized structure is subjected to small strain in different directions to calculate the Young’s modulus and other moduli of the CNT-BECy resin composite. The process is repeated for different quantities of SWCNT in BECy resin to obtain their moduli. Further, tensile and shear strengths of CNT-BECy are obtained by subjecting the equilibrated structure to a series of applied strains from 0 to 10% in steps of 1%. The stress values corresponding to each strain are obtained and a stress – strain curve is plotted. From the stress- strain curve, the strengths of the CNT -BECy which is the stress corresponding to the modulus after which the material starts to soften are determined. Effects of functionalization on mechanical properties of SWCNT are observed. Further, effects of functionalization of SWCNT are studied with a specific quantity of fSWCNT on different moduli and strengths of BECy are investigated. The properties of enhanced CNT–BECy nanocomposite resin with different quantities of added CNT obtained through MD are used to estimate the mechanical properties of the CNT-BECy-CFRP nanocomposite using micromechanics model. Further, validation with experimental results is attempted comparing the trends in enhancement of properties of the CNT-BECy resin and CNT-BECy-CFRP nanocomposite system. The outcome of this research work has been significantly positive in terms of i) Development of an appropriate process establishing different parameters for dispersing CNTs in the resin system, mixing, curing cycle for making of nanocomposites demonstrating significant and consistent enhancement of mechanical properties of BECy based resin system and CFRP nanocomposites using optimum quantity of CNTs /fCNTs through a series of well planned and executed experimental investigations. Evaluation of mechanical properties for each of the cases has been carried out experimentally. ii) Establishing a computational methodology involving intricate atomistic modelling and molecular dynamics of nanosystems for estimation of mechanical properties of BECy polymer resin and to study the effects by addition of SWCNT / functionalized SWCNT on the properties. Results obtained through series of experimental investigations have been validated through this computational study. This could be an important step towards realising the potential of this resin system for high performance aerospace applications. Thus, in brief, detailed experimental work combined with computational studies performed as presented in this thesis resulted in achieving structurally efficient cyanate ester based nanocomposites which is unique and not reported in open literature.

Indiana University-Purdue University Indianapolis (IUPUI) / Reduction of the polymerization shrinkage stress inherent of dimethacrylate-based resin composites has been a work in progress since the phenomenon was first described by Dr. Rafael L. Bowen in 1967. Contemporary efforts to modify the composites or the curing protocols for polymerization have proven a challenging task with controversial results. Influenced by existing mathematical models relating exposure, curing time and depth of cure of resin composites, a novel method for the reduction of polymerization shrinkage stress is proposed. By polymerizing through a single aperture mask, a dental light curing unit is transformed from a planar light source to a point light source, and a fully cured, three-dimensional “bullet” shaped curing front is predicted for the cured resin below. So long as the edges of the bullet do not touch the cavity walls or floor, the shrinkage stress of the bullet is not transferred. Follow-up with an unmasked curing unit then fully polymerizes the restoration. By reducing the volume of uncured composite in contact with the cavity walls and floor, shrinkage stress of the restoration is also reduced. The objective of the present study was to demonstrate this curing phenomenon with a model resin composite using masks with aperture diameters of 0.5, 0.4, and 0.25 mm and curing times of 10, 20, 30, and 40 seconds. The resulting curing front was evaluated quantitatively and qualitatively. From this, mathematical models of the curing front were derived. Selected combinations of aperture mask and curing time were then investigated to evaluate the influence of this phenomenon on the degree of conversion, Knoop hardness, and polymerization shrinkage stress of the same model resin composite. Group differences were analyzed using a one-way ANOVA at 5% significance.

No description available.

Cette thèse porte sur l’évaluation de l’impact de certains composés environnementaux sur la fécondité féminine, tel que mesuré par le délai de conception (« time to pregnancy » en anglais, ou TTP). Cette recherche a été réalisée dans le cadre de l’Étude mère-enfant sur les composés chimiques de l’environnement (MIREC), une cohorte de grossesse de 2001 femmes recrutées durant le premier trimestre dans dix villes canadiennes de 2008 à 2011. Les données des questionnaires et les échantillons biologiques ont servi à évaluer l’effet de deux groupes de composés : les persistants [composés perfluorés – perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA) et perfluorohexane sulfonate (PFHxS)] et les non persistants (bisphénol A, triclosan et phtalates). Cette thèse comprend également une analyse du potentiel du ratio index-annulaire (2D:4D) comme mesure de sensibilité endocrinienne. À ce jour, des mesures anthropométriques ont été collectées sur environ 800 mères-enfants dans le cadre de l’Étude mère-enfant sur les composés chimiques de l’environnement : biomonitoring et neurodéveloppement à la petite enfance (MIREC CD Plus), un suivi de la cohorte MIREC portant sur la croissance et le développement des enfants jusqu’à 5 ans. Sur l’ensemble, les résultats de cette thèse permettent d’étoffer les preuves concernant les effets adverses potentiels de plusieurs contaminants environnementaux sur la fécondité féminine, telle que mesurée par le TTP. Dans le premier article, nous avons montré une association entre les PFOA et les PFHxS et une baisse de fécondité, ce que d’autres recherches avaient déjà révélé. Dans le deuxième article, nous avons évalué l’effet du triclosan sur le TTP, ce qui n’avait jamais été examiné, pour montrer un délai plus élevé chez les femmes du quartile supérieur d’exposition. De plus, nos résultats sont en accord avec ceux de la seule étude ayant évalué l’effet du Bisphénol A sur la fécondité féminine, qui n’avait pas détecté d’effet. Finalement, nos données semblent indiquer une association entre l’exposition des femmes aux phtalates et un TTP plus court, mais ces résultats ne sont pas statistiquement significatifs. En ce qui a trait au potentiel du ratio index-annuaire (2D:4D) pour mesurer la sensibilité endocrinienne chez les femmes, nos données ne permettent pas d’établir une association entre ce ratio et le TTP. Pour ce qui est des enfants, nous n’avons pas trouvé d’effet adverse entre le tabagisme de la mère durant la grossesse et leur ratio 2D:4D. Par conséquent, nos données ne semblent pas justifier l’utilisation du ratio 2D:4D pour mesurer la sensibilité endocrinienne en lien avec le potentiel reproducteur (basé sur le TTP) ou l’exposition des enfants au tabac durant le premier trimestre de grossesse. / In this thesis, we aimed to evaluate the impact of selected environmental compounds on female fecundity as measured by time to pregnancy (TTP). This research was conducted in the framework of the Maternal-Infant Research on Environmental Chemicals (MIREC) study, a pregnancy cohort of 2001 women recruited during the first trimester of pregnancy in ten cities across Canada between 2008 and 2011. Questionnaire data and biological samples were analyzed to assess the effect of two groups of compounds: persistent [perfluorinated compounds - perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexane sulfonate (PFHxS)-] and nonpersistent chemicals (Bisphenol A, Triclosan, and phthalates). In addition, this thesis aimed to examine the potential of the second to fourth finger digit ratio (2D:4D) as a sensitive-endocrine endpoint. To this end, anthropometric measurements were obtained in about 800 children and their mothers during the Early Childhood Biomonitoring and Neurodevelopment Study (MIREC-CD Plus), a MIREC follow-up conducted to measure growth and development up to age five. Overall, the results of this thesis have contributed to the evidence regarding the potential adverse effect of several environmental contaminants (ECs) on female fecundity as measured by TTP. In the first article, we found that PFOA and PFHxS were associated with diminished fecundity, supporting previous evidence that suggested a similar effect. In the second article, we assessed for the first time the effect of Triclosan on TTP, presenting evidence of delayed fecundity at the highest quartile of exposure. In addition, our findings agreed with those of the only study that has assessed the effect of Bisphenol A on female fecundity, and which showed no effect. Finally, we found some indication that female exposure to phthalates might be associated with a shorter TTP, although this finding did not reach statistical significance. With regard to the potential of the digit length ratio (2D:4D) as an endocrine-sensitive endpoint in women, our data do not support a strong association between 2D:4D and TTP. In children, we did not find an adverse impact of maternal smoking during pregnancy on children’s 2D:4D. Thus, our data do not support evidence to suggest that 2D:4D could be used as a potential reproductive endocrine-sensitive endpoint in women as measured by TTP, and in their offspring as measured by exposure to maternal smoking during the first trimester of pregnancy.

Ce travail a consisté à analyser, par des approches toxicocinétiques (TK) et mécanistiques, les effets oestrogéniques du Bisphenol A (BPA) sur un biomarqueur précoce et sensible : la sécrétion de l'hormone lutéinisante (LH) chez la brebis prépubère ovariectomisée. La plus faible concentration plasmatique en BPA induisant une inhibition de LH s'est avérée proche des concentrations maximales décrites chez l'Homme. Cette inhibition de LH pourrait impliquer une inhibition des systèmes neuronaux à kisspeptine. L'approche TK comparative d'espèces a montré que la clairance du BPA est toujours élevée, proche du débit sanguin hépatique. Pour une exposition à la dose journalière admissible, cette approche permet de prédire chez l'Homme des concentrations en BPA très inférieures à celles associées à une inhibition de LH dans notre modèle. / The goal of this thesis was to analyse through toxicokinetic (TK) and mechanistic approaches the estrogeno-mimetic effects of bisphenol A (BPA) on a precocious and sensitive biomarker: LH secretion in ovariectomized female lambs. The lowest plasma BPA concentrations associated to an inhibition of LH secretion appeared to be close to the highest one reported in human. LH suppression could be mediated by an inhibition of hypothalamic kisspeptin systems. The multispecies TK approach showed that BPA clearance is always high and equivalent to the liver blood flow. For an exposure scheme corresponding to the tolerable daily intake, this approach allows to predict human BPA concentration much lower than the one associated to LH inhibition in our highly sensitive lamb model.