Serum persistent organic pollutants and diminished ovarian reserve: a single-exposure and mixture exposure approach from a French case-control study.

STUDY QUESTION: Are persistent organic pollutants (POPs) associated with a diminished ovarian reserve (DOR) in women of reproductive age? SUMMARY ANSWER: Amongst 17 POPs detected in over 20% of serum samples, only p,p'-DDE was significantly associated with an increased risk of DOR, and ß-hexachlorocyclohexane (ß-HCH) was significantly associated with a decreased risk of DOR whilst mixture analyses yielded non-significant associations and did not detect any interactions between POPs. WHAT IS KNOWN ALREADY: Animal studies have shown that several POPs can alter folliculogenesis and increase follicle depletion. However, only a few studies have been conducted in humans, with small sample sizes and inconsistent results. STUDY DESIGN, SIZE, DURATION: Our study included 138 cases and 151 controls from the AROPE case-control study. Study participants were women between 18 and 40 years of age recruited amongst couples consulting for infertility in four fertility centres in western France between 2016 and 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cases of DOR were defined as women with anti-Müllerian hormone (AMH) levels ≤1.1 ng/ml and/or antral follicle count (AFC) <7, and controls were women with AMH levels between 1.1 and 5 ng/ml and AFC ≥ 7, without genital malformations and with a menstrual cycle length between 26 and 35 days. A total of 43 POPs (including 15 organochlorine pesticides, 17 polychlorinated biphenyls, and 9 polybromodiphenylethers) were measured in the serum at inclusion into the study. We conducted logistic regression adjusted for potential confounders using a directed acyclic graph to study the effect of each POP on DOR as single exposures, and used Bayesian kernel machine regression (BKMR) to measure the mixture effect of POPs on DOR. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 43 POPs, 17 were detected in over 20% of the serum samples. In the single-exposure multivariate logistic regressions, p,p'-DDE (median 165.0 IQR 161.0 ng/l in controls) as a continuous exposure was significantly associated with an increased risk of DOR (odds ratio (OR) 1.39, 95% CI 1.10-1.77) and non-significantly associated with an increased risk of DOR for the second and third terciles (OR 1.46, 95% CI 0.74-2.87, and OR 1.72, 95% CI 0.88-3.37, respectively). ß-HCH (median 24.2 IQR 21.5 ng/l in controls) was significantly associated with a decreased risk of DOR when ß-HCH was treated as a continuous exposure (OR 0.63, 95% CI 0.44-0.89) and for the third tercile of exposure (OR 0.43, 95% CI 0.21-0.84) and non-significantly associated with a decreased risk of DOR for the second tercile (OR 0.77, 95% CI 0.42-1.42). All sensitivity analyses confirmed our results. BKMR showed similar associations for single exposures but found no significant associations for the total mixture effect. In addition, the BKMR results did not suggest any interactions between POPs. LIMITATIONS, REASONS FOR CAUTION: Controls were recruited amongst infertile couples and thus may not be representative of all women of reproductive age. However, their POP concentrations were in the same range as in the general French population. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to examine the associations between serum POPs and DOR. The well-recognized anti-androgenic properties of p,p'-DDE and estrogenic properties of ß-HCH could explain these associations of opposite direction. If these results are replicated elsewhere, this could have an impact on fertility prevention messages and help in understanding the impact of POPs on the female reproductive system. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Fondation de France (grant numbers 2014-50537 and 00110196) and the French Biomedicine Agency (2016). None of the authors have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Simultaneous exposure to both Zika virus and household insecticides during pregnancy, and fetal growth and infant developmental behavior outcomes at 18 months, in Guadeloupe.

BACKGROUND: Perinatal infection with Zika virus (ZIKV) could result in adverse growth, developmental and behavioral outcomes, while insecticides used to control mosquitoes are neurotoxic. OBJECTIVES: We aim to study the role played by exposure during pregnancy to both ZIKV and household insecticides in newborn health, development and behavior at age of 18 months. METHODS: Maternal and cord blood samples from a cohort of pregnant women (created during Guadeloupe's Zika epidemic of 2016) were used to identify ZIKV infection during pregnancy. A self-administered questionnaire at birth documented prenatal household use of insecticides. Birth weight and head circumference were collected from maternity records (n = 708). Infant development and behaviors were documented at 18 months of age through the Ages and Stages Questionnaire and the Quebec Longitudinal Study of Child Development (n = 409). Logistic and linear regression models were performed, taking into account confounding factors. RESULTS: Use of household insecticides was associated with smaller head circumference and lower birth weight among newborns from mothers not exposed to ZIKV: 0.3 cm (95% CI: 0.6, 0) and -82 g (95% CI: 165, 0), respectively. Similar decreases were observed with ZIKV exposure among mothers not reporting household insecticides use, and with presence of both exposures. The combined presence of ZIKV exposure and insecticide use was associated with lower ASQ fine motor scores (-3.9; 95% CI: 7.3, -0.4), and higher hyperactivity scores (0.8; 95% CI: 0.0, 1.5), compared to no exposure to either. A higher opposition score was observed in association with ZIKV exposure among non-users of insecticide (0.6; 95% CI: 0.0, 1.2). CONCLUSION: Adverse neurodevelopmental outcomes at 18 months of age were observed with prenatal ZIKV exposure, and with higher magnitude when mothers reported use of household insecticides. At birth, rates of adverse fetal growth were however similar for the combined presence of exposure and either of the exposures.

Association between exposure to persistent organic pollutants and mercury, and glucose metabolism in two Canadian Indigenous populations.

BACKGROUND: The body burden of metals and persistent organic pollutants (POPs) is particularly high in populations that rely on fish and other marine species for sustenance. This exposure has been associated with an increased risk of type 2 diabetes, but results remain contrasted. OBJECTIVE: We studied this association in two Indigenous populations of northern Québec (Canada) with markedly different prevalences of diabetes and levels of exposure to POPs and mercury. METHODS: As part of health surveys conducted in 2004-2009, diabetes prevalence and glucose metabolism (glucose, insulin, HOMA-IR, HOMA-B) in non-diabetic fasting adults were assessed using similar protocols in two populations: Inuit from Nunavik (n = 877) and Cree from Eeyou Istchee territory (n = 780). Blood mercury, plasma polychlorinated biphenyls (PCBs), organochlorine (OC) pesticides/metabolites and polybrominated diphenylethers (PBDEs) levels were measured in samples collected at the time of examination. Logistic and linear regressions and restricted cubic splines analyses were conducted adjusting for sex, age, waist circumference, smoking and omega-3 fatty acid content in plasma phospholipids. RESULTS: Diabetes prevalence was higher in Cree (20%) than in Inuit (7%), whereas environmental exposure was 2 to 3-fold greater in Inuit than in Cree participants. In the range of exposure common to the two populations, we observed similar linear increases in the risk of diabetes with increasing contaminant exposure. Among Cree participants, fasting glucose was positively associated with plasma PBDE level, and HOMA-B negatively associated with concentrations of ∑PCBs, dichlorodiphenyldichloroethylene, PBDEs and ∑OC pesticides. Among Inuit participants, a trend towards reduced insulin secretion was observed in association with most contaminants, but the relation was nonlinear (greater reduction at intermediate levels of exposure). A significant increase in fasting glucose levels was observed at elevated blood mercury levels (>16 µg/L). CONCLUSION: The observed association between POPs exposure and diabetes risk in the two populations studied should be confirmed using prospective design. Our results suggest the need for additional research on the physiopathological process through which POPs exposure may induce type 2 diabetes in these Indigenous populations.

Exposure of pregnant women to organophosphate insecticides and child motor inhibition at the age of 10-12 years evaluated by fMRI.

BACKGROUND: Organophosphate pesticides (OP) are widely used for both agricultural and domestic purposes. Epidemiological studies suggest neurotoxicity in children after exposure to organophosphates pesticides (OP) at low levels but possible mechanism is still unclear. OBJECTIVES: We aimed at investigating the effects of prenatal exposure to OPs on inhibitory control of 10-12 year-old-children assessed by a motor inhibition task during functional magnetic resonance imaging (fMRI). METHODS: Ninety-five children from the PELAGIE cohort (Brittany-France, from 2002) underwent a fMRI examination during which inhibition was assessed by a Go/No-Go task. Task performance was assessed by average response latency, commission rate and composite performance score (PS). Whole brain activation was estimated by modeling the hemodynamic response related to inhibition demand and successful inhibition. OP exposure was assessed by measuring six dialkylphosphate (DAP) metabolites in the urine of women in early pregnancy (<19 WG). Concentrations were summed to obtain overall levels of diethylphosphate (DE), dimethylphosphate (DM) and total non-specific metabolites (DAP), standardized to homogenize sampling conditions and categorized into levels of exposure: low (reference), moderate or high. Regression models were adjusted for potential cofounders considered by restriction and statistical criteria. RESULTS: Moderate levels of DAP were associated with a decreased commission rate (ß = -6.65%, p = 0.04), indicating improved performance. Increasing levels of DM and DE were associated with decreased brain activity in the left inferior and bilateral superior frontal regions during successful inhibition. We did not observe any differential activation related to inhibitory demands. DISCUSSION: These results suggest that prenatal OPs may be associated with altered pattern of brain activity in regions related to inhibition among children and need to be confirmed by additional studies.

How a dc Electric Field Drives Mott Insulators Out of Equilibrium.

Out of equilibrium phenomena are a major issue of modern physics. In particular, correlated materials such as Mott insulators experience fascinating long-lived exotic states under a strong electric field. Yet, the origin of their destabilization by the electric field is not elucidated. Here we present a comprehensive study of the electrical response of canonical Mott insulators GaM_{4}Q_{8} (M=V, Nb, Ta, Mo; Q=S, Se) in the context of a microscopic theory of electrical breakdown where in-gap states allow for a description in terms of a two-temperature model. Our results show how the nonlinearities and the resistive transition originate from a massive creation of hot electrons under an electric field. These results give new insights for the control of the long-lived states reached under an electric field in these systems which has recently open the way to new functionalities used in neuromorphic applications.

Elastic Softness of Hybrid Lead Halide Perovskites.

Much recent attention has been devoted towards unraveling the microscopic optoelectronic properties of hybrid organic-inorganic perovskites. Here we investigate by coherent inelastic neutron scattering spectroscopy and Brillouin light scattering, low frequency acoustic phonons in four different hybrid perovskite single crystals: MAPbBr_{3}, FAPbBr_{3}, MAPbI_{3}, and α-FAPbI_{3} (MA: methylammonium, FA: formamidinium). We report a complete set of elastic constants characterized by a very soft shear modulus C_{44}. Further, a tendency towards an incipient ferroelastic transition is observed in FAPbBr_{3}. We observe a systematic lower sound group velocity in the technologically important iodide-based compounds compared to the bromide-based ones. The findings suggest that low thermal conductivity and hot phonon bottleneck phenomena are expected to be enhanced by low elastic stiffness, particularly in the case of the ultrasoft α-FAPbI_{3}.

Exposure of pregnant women to persistent organic pollutants and cord sex hormone levels.

STUDY QUESTION: Is prenatal exposure to persistent organic pollutants (POPs) associated with variations of sex hormone levels in cord blood? SUMMARY ANSWER: Prenatal exposure to a number of POPs is associated with a disruption of hormone levels in cord blood, with sex specificities. WHAT IS KNOWN ALREADY: Epidemiological studies have reported disorders of reproductive health, in relation with POPs exposure during early life and the endocrine disruption properties of these chemicals have been suggested as possible mechanisms. STUDY DESIGN, SIZE, DURATION: A subset of 282 mother-child pairs was selected from the prospective population-based PELAGIE birth cohort (n = 3421, 2002-2006, Brittany, France). Pregnant women were recruited before 19 weeks of gestation and followed until delivery. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sex hormone levels including sex hormone-binding globulin (SHBG), estradiol (E2), total testosterone (T), free testosterone (fT = T/SHBG) and the aromatase index (AI = T/E2) were measured in 282 cord blood samples. Anti-Müllerian hormone (AMH) was measured in male newborns only. Pesticide concentrations of α-endosulfan, ß-hexachlorocyclohexane (ß-HCH), γ-HCH, dieldrin, pp'-dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzene (HCB), heptachlor epoxide (HCE), as well as PCBs (congeners 153, 187 and the sum of anti-estrogenic PCBs 118, 138, and 170) and decabrominated diphenyl ether (BDE209) were also measured in cord blood. Associations between sex hormones and POPs exposure were explored using multiple linear regressions adjusted for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: High PCB levels were associated with an increase of SHBG (P-trend < 0.01) and AMH (P-trend < 0.05) and a decrease of fT (P-trend < 0.05) and AI (P-trend < 0.01). High pesticide levels, particularly α-endosulfan and HCE, were associated with an increase of SHBG (P < 0.05) and E2 (P < 0.01) and a decrease of fT (P < 0.05) and AI (P < 0.01). Several of these associations were stronger, or specific, among male or female newborns. The associations were not altered in the sensitivity analyses. LIMITATIONS, REASONS FOR CAUTION: The study population was of relatively small sample size, and some compounds rarely detected in cord blood. The high level of correlation between POPs makes it difficult to identify the most contributing POPs. Hormone measurements were performed at birth (in cord blood) and may not adequately represent the infant endocrine system. Multiple statistical testing may have led to false-positive associations. WIDER IMPLICATIONS OF THE FINDINGS: Our results are in discordance with those reported in the only published study of the kind but in accordance with studies about prenatal exposure to other endocrine disruptors such as phthalates. These findings may help understanding the pathways involved in adverse reproductive outcomes associated with POPs exposure. STUDY FUNDING/COMPETING INTERESTS: The PELAGIE cohort is funded by Inserm, French Ministry of Health, French Ministry of Labor, InVS, ANR, ANSES, and French Ministry of Ecology. None of the authors has any competing interest to declare.

Efficient active waveguiding properties of Mo6 nano-cluster-doped polymer nanotubes.

We investigate 1D nanostructures based on a Mo6@SU8 hybrid nanocomposite in which photoluminescent Mo6 clusters are embedded in the photosensitive SU8 resist. Tens of micrometers long Mo6@SU8-based tubular nanostructures were fabricated by the wetting template method, enabling the control of the inner and outer diameter to about 190 nm and 240 nm respectively, as supported by structural and optical characterizations. The image plane optical study of these nanotubes under optical pumping highlights the efficient waveguiding phenomenon of the red luminescence emitted by the clusters. Moreover, the wave vector distribution in the Fourier plane determined by leakage radiation microscopy gives additional features of the emission and waveguiding. First, the anisotropic red luminescence of the whole system can be attributed to the guided mode along the nanotube. Then, a low-loss propagation behavior is evidenced in the Mo6@SU8-based nanotubes. This result contrasts with the weaker waveguiding signature in the case of UV210-based nanotubes embedding PFO (poly(9,9-di-n-octylfluorenyl-2,7-diyl)). It is attributed to the strong reabsorption phenomenon, owing to overlapping between absorption and emission bands in the semi-conducting conjugated polymer PFO. These results make this Mo6@SU8 original class of nanocomposite a promising candidate as nanosources for submicronic photonic integration.

Combined theoretical and time-resolved photoluminescence investigations of [Mo6Brⁱ8Br(a)6]²â» metal cluster units: evidence of dual emission.

The combined time-resolved photoluminescence (PL) and theoretical study performed on luminescent [Mo6Br(i)8Br(a)6](2-)-based systems unambiguously shows that their NIR-luminescence is due to at least two emissive states. By quantum chemical studies, we show for the first time that important geometrical relaxations occur at the triplet states either by the outstretching of an apex away from the square plane of the Mo6 octahedron or by the elongation of one Mo-Mo bond. Experimental PL measurements demonstrate that the external environment (counter-ions, crystal packing) of the cluster has a noticeable impact on its relaxation processes. Temperature and excitation wavelength dependence of the two components of the luminescence spectra is representative of multiple competitive de-excitation processes in contradiction with Kasha's rule. Our results also demonstrate that the relaxation processes before and after emission can be tracked via fast time-resolved spectroscopy. They also show that the surroundings of the luminescent cluster unit and the excitation wavelength could be modulated for target applications.

International geographic correlation study of the prevalence of disorders of male reproductive health.

STUDY QUESTION: Is there evidence at the population level of associations between different male genital disorders, outside Scandinavian countries? SUMMARY ANSWER: At an international scale, there is evidence for a number of correlations between rates of four male reproductive disorders (hypospadias, cryptorchidism, testicular cancer and low sperm concentration). WHAT IS KNOWN ALREADY: Some associations between these outcomes have been shown in studies focusing on individuals and mainly in Nordic European countries. These associations, together with histological evidence of a dysgenesis pattern in testicular tissue specimens, have generated the concept of the existence of a 'testicular dysgenesis syndrome' originating in utero. STUDY DESIGN, SIZE, DURATION: This is a geographical correlation study using cancer, malformations rates and sperm quality data collected between the years 1998 and 2005. PARTICIPANTS/MATERIALS, SETTING, METHODS: Incidence rates of testicular cancer were extracted from International Agency for Research on Cancer registries and Globocan, while cryptorchidism and hypospadias prevalence rates were obtained from EUROCAT and International Clearinghouse for Birth Defects Surveillance and Research registries. Sperm concentration data were extracted from recent studies using standardized methodology. A total of 39 registries and 9 sperm studies were selected. Non-parametric Spearman correlation tests were used to test the association between these four disorders. Correlations were computed for all registries together, for registries with high-quality matching coverage only and by continents. Sensitivity analyses were also conducted using data from prospective clinical studies to take into account potential bias related mainly to ascertainment of malformation rates. MAIN RESULTS AND THE ROLE OF CHANCE: We found positive correlations between testicular cancer and hypospadias (r = 0.32, P = 0.05) and between hypospadias and cryptorchidism (r = 0.70, P = 0.008). Stronger correlations were observed when using registries with high-quality matching coverage. Among these registries, differences between Europe and the rest of the world appeared (the positive correlation between testicular cancer and cryptorchidism was stronger outside Europe, r = 0.83, P = 0.01 compared with 0.40, P = 0.60 for European registries). A negative correlation between testicular cancer and sperm concentration was observed (r = -0.88, P = 0.002). These correlations support our initial hypothesis but remain only suggestive due to the intrinsic limitations in the study design (i.e. geographical correlation study) and do not allow causal inference. LIMITATIONS, REASONS FOR CAUTION: Differences in the ascertainment of malformations rates (definition, length of follow-up) make the international comparison difficult. The small number of registries for some conditions (cryptorchidism) or of studies (for sperm quality) and the absence of information about major risk factors such as ethnicity and socioeconomic status in the registries are also limitations. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are in agreement with results of studies focusing on individuals and suggest that shared risk factors are present in the populations studied.

Medical and sociodemographic risk factors for preterm birth in a French Caribbean population of African descent.

There appears to be an incompressible high rate of preterm births among populations of African origin irrespective of their geographic location. The objective of this study was to assess the risk factors for preterm birth in a French Caribbean population of African descent, offered medical care comparable to that on the French mainland, but presenting a higher rate of preterm birth. The study was based on a birth cohort at maternity hospitals in Guadeloupe (French West Indies) including 911 singleton pregnancies enrolled during their third trimester check-up visits. Associations between risk factors and the risk of preterm delivery (spontaneous and induced) were assessed using a multivariate Cox model. In addition, prevalences of sociodemographic and medical factors in Guadeloupe were compared with those on the French mainland. 144 women (15.8 %) delivered preterm, medically induced in 52 %. Women delivering preterm were more often over 35 years old (37 %), single (54 %), and had higher prevalence of prior preterm birth (20 %), prior miscarriage (37 %), lupus (3 %), asthma (14 %), gestational hypertension (26 %), gestational diabetes (13 %) and urinary tract infection (24 %) than women with term births. In the whole cohort, these risk factors were also more frequent than in mainland France. Our results suggest highly prevalent medical risk factors for preterm births in Guadeloupe. This observation combined with specific social risk factors (older maternal age, single living) less frequent on the French mainland probably explains a large part of a higher prevalence of preterm births in this population despite similar medical provision.

Antiferromagnetic Ordering of Magnetic Clusters Units in Nb(6)F(15).

We have studied the magnetic cluster compound Nb(6)F(15) which has an odd number of 15 valence electrons per (Nb(6)F(12))(3+) cluster core, as a function of temperature using nuclear magnetic resonance, magnetic susceptibility, electron magnetic resonance and neutron powder diffraction. Nuclear magnetic resonance of the (19)F nuclei shows two lines corresponding to the apical F(a-a) nucleus, and to the inner F(i) nuclei. The temperature dependence of the signal from the F(i) nuclei reveals an antiferromagnetic ordering at T < 5 K, with a hyperfine field of ~2 mT. Magnetic susceptibility exhibits a Curie-Weiss behavior with T(N) ~5 K, and µ(eff) ~1.57 µ(B) close to the expected theoretical value for one unpaired electron (1.73 µ(B)). Electron magnetic resonance linewidth shows a transition at 5 K. Upon cooling from 10 to 1.4 K, the neutron diffraction shows a decrease in the intensity of the low-angle diffuse scattering below Q ~0.27 Å(-1). This decrease is consistent with emergence of magnetic order of large magnetic objects (clusters). This study shows that Nb(6)F(15) is paramagnetic at RT and undergoes a transition to antiferromagnetic order at 5 K. This unique antiferromagnetic ordering results from the interaction between magnetic spins delocalized over each entire (Nb(6)F(12) (i))(3+) cluster core, rather than the common magnetic ordering.

Infant neurodevelopment and behavior in Guadeloupe after lead exposure and Zika maternal infection during pregnancy.

BACKGROUND: Prenatal lead exposure is known to have neurotoxic effects on the developing fetus, while some viral infections may have a tropism for the central nervous system. Our objective was to study whether the effects of prenatal lead exposure on infant development and behaviors at 18 months of age are modified by the occurrence of a maternal infection to Zika virus (ZIKV) during pregnancy. METHODS: During the ZIKV epidemic in Guadeloupe in 2016 a cohort of pregnant women was set up. Blood samples (pregnancy, childbirth and cord) (n = 297) enabled us to measure blood lead levels aimed to determine prenatal lead exposure and the likelihood of maternal infection during pregnancy (ZIKV status + vs -). The 18 months "Ages and Stages Questionnaire" (ASQ) was used to generate scores for global development, fine and gross motor skills, communication, problem solving, and personal-social skills. The questions from a longitudinal cohort study conducted in Canada (Québec) were used to generate hyperactivity, opposition, inattention and physical aggression scores. Associations were tested by multivariate linear regressions. RESULTS: Prenatal lead exposure was associated with delays in neurodevelopment at 18 months, reflected by lower scores in ASQ totals, and in the fine motor and problem-solving domains. Some of these associations appeared to be sex-specific, observed almost exclusively in boys (ASQ total, fine motor and personal-social scores). Prenatal lead exposure was not associated with behavioral scores. ZIKV infection during pregnancy was associated with a lower fine motor ASQ score, and higher scores for hyperactivity, opposition and physical aggression. Significant interaction between prenatal lead exposure and ZIKV status was observed with a lower personal-social score in ZIKV (-) only, and for hyperactivity and inattention scores, though some of these interactions (ASQ personal-social score, inattention score) were no longer significant when children with microcephaly were excluded from the analyses. DISCUSSION/CONCLUSION: Our study confirms previous findings of associations between prenatal exposure to lead at low levels and adverse neurodevelopmental outcomes during infancy and the particular vulnerability of boys. It suggests associations between ZIKV infection during pregnancy and adverse effects on a number of neurodevelopmental functions (fine motor function) and behaviors (opposition, hyperactivity), that need to be confirmed at later age. There is no strong evidence of interaction between ZIKV infection and lead exposure but both prenatal risk factors may affect fine motor function.

Influence of fetal glutathione S-transferase copy number variants on adverse reproductive outcomes.

A nested case-control association study was designed to investigate the influence of maternal and fetal copy number variants (CNVs) on reproductive outcomes. Genotypes of ten CNVs encompassing GST and CYP genes were assessed. Significant associations were only found for child CNV genotypes. In particular, the child GSTM1 insertion allele was associated with prematurity protection (odds ratio, 95% CI: 0.67, 0.51-0.89; P < 0.01), whereas the child GSTT2B insertion allele was associated with an increased risk of being small for gestational age (odds ratio, 95% CI: 1.33, 1.07-1.67; P = 0.01). The study highlights the role of the fetal genome in prenatal development and also the need to analyse CNVs in a systematic manner.

Molybdenum-Iodine Cluster Loaded Polymeric Nanoparticles Allowing a Coupled Therapeutic Action with Low Side Toxicity for Treatment of Ovarian Cancer.

The ability of cancer cells to develop resistance to anti-cancer drugs, known as multidrug resistance, remains a major cause of tumor recurrence and cancer metastasis. This work explores the double mechanism of toxicity of (D, L-lactide-co-glycolide) acid (PLGA) nanoparticles encapsulating a molybdenum cluster compound, namely Cs2[{Mo6I8}(OOCC2F5)6] (CMIF). Hemocompatibility and biocompatibility assays show the safe potential of CMIF loaded nanoparticles (CNPs) as delivery systems intended for tumor targeting for PDT of ovarian cancer with a slight hemolytic activity and a lack of toxicity up to 50 µM CMIF concentration. Cellular uptake shows a preferential uptake of CNPs in lysosomes, which is not interfering with CMIF activity. The double mechanism of CNPs consists in a production of ROS and a DNA damage activity, from 5 µM and 0.5 µM respectively (CMIF concentration). The cellular death mechanism comprises 80% of necrosis and 20% of direct apoptosis by direct DNA damages. This work confirms CMIF loaded PLGA nanoparticles as an efficient and relevant delivery system for PDT.

Water disinfection by-products and bladder cancer: is there a European specificity? A pooled and meta-analysis of European case-control studies.

Several epidemiological studies suggested an association between the risk of bladder cancer and the exposure to trihalomethanes (THMs), the main disinfection by-products (DBPs) of chlorinated water. A previous pooled analysis of case-control studies from North America and Europe estimated a summarized dose-response relation. For policy guidance of drinking water disinfection in Europe and because major differences exist in water disinfection practices and DBPs occurrence between both continents, specific risk estimates for bladder cancer in relation to DBPs exposure for European populations were needed. We conducted a pooled and a two-stage random-effect meta-analyses of three European case-control studies from France, Finland, and Spain (5467 individuals: 2381 cases and 3086 controls). Individual exposure to THMs was calculated combining information on residential history, estimates of the average total THMs (TTHM) level in tap water at the successive residences and personal water consumption. A significant odds-ratio was observed for men exposed to an average residential TTHM level > 50 µg/l (OR = 1.47 (1.05; 2.05)) when compared to men exposed to levels ≤ 5 µg/l. The linear trend of the exposure-risk association was significant (p = 0.01). Risks increased significantly for exposure levels above 25 µg/l and with more than 30 years of exposure to chlorinated water, but were mainly driven by the level rather than the duration of exposure. No significant association was found among women or with cumulative exposure through ingestion. There was no evidence of a differential exposure-response relation for TTHM and bladder cancer in Europe and North America. Consequently, a global exposure-risk relation based on 4351 cases and 7055 controls is now available.

From molecules to nanovectors: Current state of the art and applications of photosensitizers in photodynamic therapy.

Photodynamic therapy (PDT) is a concept based on a selective activation by light of drugs called photosensitizers (PS) leading to reactive oxygen species production responsible for cell destruction. Mechanisms of photodynamic reaction and cell photo-destruction following direct or indirect mechanisms will be presented as well as PS classification, from first generation molecules developed in the 1960 s to third generation vectorized PS with improved affinity for tumor cells. Many clinical applications in dermatology, ophthalmology, urology, gastroenterology, gynecology, neurosurgery and pneumology reported encouraging results in human tumor management. However, this interesting technique needs improvements that are currently investigated in the field of PS excitation by the design of new PS intended for two-photon excitation or for X-ray excitation. The former excitation technique is allowing better light penetration and preservation of healthy tissues while the latter is combining PDT and radiotherapy so that external light sources are no longer needed to generate the photodynamic effect. Nanotechnology can also improve the PS to reach the tumor cells by grafting addressing molecule and by increasing its aqueous solubility and consequently its bioavailability by encapsulation in synthetic or biogenic nanovector systems, ensuring good drug protection and targeting. Co-internalization of PS with magnetic nanoparticles in multifunctional vectors or stealth nanoplatforms allows a theranostic anticancer approach. Finally, a new category of inorganic PS will be presented with promising results on cancer cell destruction.

Molybdenum cluster loaded PLGA nanoparticles as efficient tools against epithelial ovarian cancer.

In this study, poly (lactic-co-glycolic) acid nanoparticles loading inorganic molybdenum octahedral cluster were used for photodynamic therapy (PDT) of ovarian cancer. Three cluster compounds, ((C4H9)4N)2[{Mo6Br8}Br6], Cs2[{Mo6Br8}Br6] and Cs2[{Mo6I8}(OOC2F5)6] denoted TMB, CMB and CMIF were studied following their incorporation in nanoparticles by a nanoprecipitation method. All resulting nanoparticles exhibited physico-chemical characteristics such as size and zeta potential compatible with cellular uptake. All cluster compounds tested were shown to produce singlet oxygen in vitro once released from their nanoparticulate system. Confocal images showed an internalisation of cluster loaded nanoparticles (CNPs) in A2780 ovarian cancer cell line, more efficient with CMIF compared to CMB or TMB loaded nanoparticles. In vitro cellular viability studies conducted on A2780 cell line treated with non activated CNPs did not show any sign of toxicity for concentrations up to 15 µM. Following photo-activation, CNPs were able to generate singlet oxygen resulting in a decrease of the cellular viability, compared to non-activated conditions. Nevertheless, no significant differences between IC50 with or without photo-activation were observed with TMB and CMB CNPs while for CMIF loaded nanoparticles, the photo-activation led to a significant decrease of cellular viability compared to the non activated condition and this decrease was independant of the P/C ratio. The strong photo-toxicity obtained for CMIF loaded nanoparticles with a P/C ratio of 2.5, as shown with half maximal inhibitory concentration (IC50) value near 1.8 µM suggests that PLGA nanoparticles seem to be efficient delivery systems intended for tumor management and that CMIF can be further investigated as photosensitizer for PDT of ovarian cancer.

PLGA nanoparticles embedding molybdenum cluster salts: Influence of chemical composition on physico-chemical properties, encapsulation efficiencies, colloidal stabilities and in vitro release.

We present a screening of poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles embedding a series of inorganic molybdenum octahedral clusters intended for photodynamic therapy (PDT) of cancer. Three cluster compounds from 2 cluster units, [{Mo6Br8}Br6]2- and [{Mo6I8}(OOC2F5)6]2- were studied. [{Mo6Br8}Br6]2-cluster units are found in the soluble ternary salt Cs2[{Mo6Br8}Br6] (CMB) prepared by solid state chemistry at high temperature. In solution Cs+ cations are replaced by tetrabutyl ammonium cations (C4H9)4N+) to form the salt ((C4H9)4N)2[{Mo6Br8}Br6] (TBA2). [{Mo6I8}(OOC2F5)6]2- was prepared combining solid state and solution chemistries; it is paired with Cs+ cations to form Cs2[{Mo6I8}(OOC2F5)6] (CMIF). All tested cluster-based salts could efficiently be incorporated in PLGA nanoparticles as seen with encapsulation efficiencies always higher than 60%. Cluster loaded nanoparticles (CNPs) freshly prepared by solvent displacement method showed spherical shapes, zeta potential values between -20 and -47 mV, polydispersity index in the range 0.123-0.167 and sizes in the range 75-150 nm according to the cluster compound and the polymer-to-cluster mass ratio (P/C), suggesting a good cellular uptake. CNPs colloidal stability was maintened for 3 months when they were stored refrigerated and protected from light but the chemical stability was shorter, i.e. 4 weeks, 1 week and 1 day for CMIF, TBA2 and CMB, respectively, CMIF penta-fluoropropionate apical ligands being less rapidly substituted by hydroxyles groups than TBA2 and CMB halogen apical ligands. FT-IR analysis revealed the lack of strong chemical interaction between cluster compounds and polymer within the nanoparticles. An interesting quick cluster in vitro release driven by diffusion outside the nanoparticles porous matrix was observed for all cluster compounds when P/C ratio was ≤2.5 and only a higher P/C ratio not studied in this work (i.e. >5) could significantly affect the release of the encapsulated cluster compound. Photophysical properties of cluster compounds were preserved following PLGA incorporation. This work presents PLGA nanoparticles as a stable and efficient cluster compound delivery systems for further in vitro and vivo evaluations in cancer models.

Maternal occupational exposure to solvents and congenital malformations: a prospective study in the general population.

OBJECTIVE: To study the relations between maternal occupational exposure to solvents during pregnancy and the risk of congenital malformations. METHODS: A prospective population-based cohort, specifically designed to study the impact of maternal exposure to solvents on the risk of congenital malformations, began in 2002 in three districts of Brittany (France). 3421 pregnant women were recruited until the end of 2005 by physicians before 19 weeks of gestation and followed through birth. Information on pregnancy outcomes was obtained from the hospital. Occupational exposure to solvents at the beginning of pregnancy was assessed from the women's self-reported occupational exposures at inclusion and from a job-exposure matrix (JEM). Sociodemographic characteristics, lifestyle factors, medical history, diseases during pregnancy were obtained at inclusion and from hospital records. Analyses were restricted to working women (n = 3005). Logistic regressions were used to adjust for potential confounders. RESULTS: 30.2% of the working women declared regular exposure to at least one product that may contain solvents. 21.3% of them were classified at least in the medium exposure category using the JEM. Occupations mainly classified as exposed by both assessment methods were hairdressers, nurses' aides, nurses and chemists/biologists. Significant associations were found between major congenital malformations and maternal occupational exposure to solvents, assessed by both self-report odds ratio (OR = 2.48, 95% CI 1.4 to 4.4 for regular exposure vs no exposure) and the JEM (OR = 3.48, 95% CI 1.4 to 8.4 for highest level of exposure vs no exposure). A significant dose-response trend was observed with both assessment methods. Several subgroups of major malformations were associated with maternal exposure to solvents (oral clefts, urinary malformations and male genital malformations). CONCLUSION: This study provides further evidence of an association between exposure to solvents during pregnancy and the risk of major malformations.