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.

Maternal occupational exposure to endocrine-disrupting chemicals during pregnancy and semen parameters in adulthood: results of a nationwide cross-sectional study among Swiss conscripts.

STUDY QUESTION: Is there a relationship between maternal occupational exposure to endocrine-disrupting chemicals (EDCs) during pregnancy and the semen quality of their sons? SUMMARY ANSWER: Our results suggest an association between maternal occupational exposure to potential EDCs, especially to pesticides, phthalates and heavy metals, and a decrease in several semen parameters. WHAT IS KNOWN ALREADY: Sexual differentiation, development and proper functioning of the reproductive system are largely dependent on steroid hormones. Although there is some animal evidence, studies on maternal exposure to EDCs during pregnancy and its effect on the semen quality of sons are scarce and none have focused on maternal occupational exposure. STUDY DESIGN, SIZE, DURATION: A cross-sectional study aiming to evaluate semen quality was carried out among Swiss conscripts aged 18 to 22 years between 2005 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Conscript and parent questionnaires were completed prior to the collection of a semen sample. Semen parameters were categorised according to the guidelines of the World Health Organization (WHO). Data on maternal employment during pregnancy were provided by the parent questionnaire. Maternal occupational exposure to potential EDC categories was defined using a job-exposure matrix (JEM). Logistic regressions were used to analyse the relationship between maternal occupational exposure to EDCs and each semen parameter adjusted for potential confounding factors. Results are presented using odds ratios and 95% confidence intervals. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 1,737 conscripts provided a conscript and parent questionnaire, as well as a semen sample; among these 1,045 of their mothers worked during pregnancy. Our study suggests an association between occupational exposure of mothers during pregnancy to potential EDCs and low semen volume and total sperm count, particularly for exposure to pesticides (OR 2.07, 95% CI 1.11-3.86 and OR 2.14, 95% CI 1.05-4.35), phthalates (OR 1.92, 95% CI 1.10-3.37 and OR 1.89, 95% CI 1.01-3.55), and heavy metals (OR 2.02, 95% CI 1.14-3.60 and OR 2.29, 95% CI 1.21-4.35). Maternal occupational exposure to heavy metals was additionally associated with a low sperm concentration (OR 1.89, 95% CI 1.06-3.37). LIMITATIONS, REASONS FOR CAUTION: Several limitations should be noted, such as the indirect method for maternal occupational exposure assessment during the pregnancy (JEM) and the cross-sectional design of the study. WIDER IMPLICATIONS OF THE FINDINGS: Our observations reinforce the need to inform pregnant women of potential hazards during pregnancy that could impair their child's fertility. Additional studies are needed to confirm the involvement of EDCs. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Swiss Centre for Applied Human Toxicology: SCAHT and the 'Fondation privée des Hôpitaux Universitaires de Genève'. The collection of human biological material used for this study was supported by the FABER Foundation, the Swiss National Science Foundation (SNSF): NFP 50 'Endocrine Disruptors: Relevance to Humans, Animals and Ecosystems', the Medical Services of the Swiss Army (DDPS) and Medisupport. The authors declare they have no competing financial interests. TRIAL REGISTRATION NUMBER: N/A.

Comprehensive molecular classification of localized prostate adenocarcinoma reveals a tumour subtype predictive of non-aggressive disease.

Background: Management of localized prostate cancer (PCa) is a major clinical challenge since most of these cancers would not evolve but a majority of patients will still undergo a life-changing radical surgery. Molecular studies have shown that PCa can be classified according to their genomic alterations but none of the published PCa molecular classifications could identify a subtype corresponding to non-evolutive tumours. Materials and methods: Multi-omics molecular profiling was carried out on post-radical prostatectomy material from a cohort of 130 patients with localized PCa. We used unsupervised classification techniques to build a comprehensive classification of prostate tumours based on three molecular levels: DNA copy number, DNA methylation, and mRNA expression. Merged data from our cohort and The Cancer Genome Atlas cohort were used to characterize the resulting tumour subtypes. We measured subtype-associated risks of biochemical relapse using Cox regression models and survival data from five cohorts including the two aforementioned. Results: We describe three PCa molecular subtypes associated with specific molecular characteristics and different clinical outcomes. Particularly, one subtype was strongly associated with the absence of biochemical recurrence. We validated this finding on 746 samples from 5 distinct cohorts (P = 3.41 × 10-8, N = 746 tumour samples), and showed that our subtyping approach outperformed the most popular prognostic molecular signatures to accurately identify a subset of patients with a non-evolutive disease. We provide a set of 36 transcriptomic biomarkers to robustly identify this subtype of non-evolutive cases whose prevalence was estimated to 22% of all localized PCa tumours. Conclusion: At least 20% of patients with localized PCa can be accurately predicted to have a non-evolutive disease on the basis of their molecular subtype. Those patients should not undergo immediate surgery and rather be placed under active surveillance.

Predictors of biochemical recurrence after radical prostatectomy in an Afro-Caribbean population in Guadeloupe (French West Indies).

PURPOSE: Few studies have investigated predictive risk factors of biochemical recurrence (BCR) after radical prostatectomy (RP) in other than Caucasian and Asian populations. We aimed to identify pre- and post-operative predictors of BCR after RP in an Afro-Caribbean population in Guadeloupe (French West Indies). PATIENTS AND METHODS: The study included 964 patients who underwent RP for clinically localized prostate cancer between April 1, 2000 and December 31, 2010 in the University Hospital of Guadeloupe. The hazard ratio (HR) and corresponding 95% confidence interval (CI) for single variable associations with BCR were calculated using the Cox proportional hazards regression. Multiple variable analyses for association with BCR were performed, including all variables that reached statistical significance (P value<0.05) in univariate analysis. A backward selection model was then applied with a P value ≥0.1 for retention in the final model. Sensitivity analysis was performed and restricted to patients with known values for all variables (complete case analysis). RESULTS: With a median follow-up of 4.8 years, the BCR rate was 26.7%. In multivariable analysis, predictors of BCR before surgery were diabetes mellitus type 2 (DT2) (HR: 1.37, 95% CI: 1.02-1.85; P=0.038), pre-operative PSA>7.5ng/ml (1.49, 1.15-1.92; P=0.002), clinical stage T2 (1.55, 1.21-1.98; P=0.0006), Gleason score>7 or 4+3 (2.12, 1.54-2.91; P<0.0001), and percentage of length of biopsy positive scores (1.66, 1.24-2.20; P=0.0006). Predictors of BCR after surgery were DT2 (HR: 1.37, 95% CI: 1.01-1.85; P=0.045), pre-operative PSA>7.5ng/ml (1.37, 1.06-1.79; P=0.018), pathological Gleason score>7 or 4+3 (2.36, 1.74-3.19; P<0.0001), pathological stage pT3b (1.68, 1.15-2.45; P=0.007), positive surgical margins (1.72, 1.32-2.45; P=0.0001), and perioperative blood loss>2000ml (3.74, 1.37-10.2; P=0.01). The results were virtually the same by sensitivity analysis (complete cases), except for DT2, which was associated with BCR with borderline statistical significance in the pre-operative model and not retained in the post-operative model. CONCLUSIONS: Afro-Caribbean populations in French West Indies share the same major clinical and pathological risk factors of BCR after RP identified in other ethnic groups. Perioperative blood loss appears to be an additional and independent predictive factor of BCR. LEVEL OF PROOF: 4.

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.

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.

Cervical intraepithelial neoplasia and invasive cancer risks in women infected with HIV in the French West Indies.

OBJECTIVE: The aim of the study was to assess whether HIV infection is associated with a higher risk of invasive cervical cancer (ICC). METHODS: We conducted a region-wide, population-based observational cohort study of 1232 HIV-infected women over the age of 15 years in Guadeloupe, a French Caribbean archipelago, during the period 1999-2006. The observed numbers of incident cases of cervical intraepithelial neoplasia (CIN) and ICC were compared with the expected numbers of cases based on the incidence rates for the general population, and the standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated. RESULTS: The incidence rate of CIN was higher in the HIV-infected women than in the general population for all grades (SIR 10.1, 95% CI 6.8-14.6 for CIN grade 1; SIR 9.9, 95% CI 6.1-15.3 for CIN grade 2; and SIR 5.2, 95% CI 3.4-7.7 for CIN grade 3). However, no increase in the risk of ICC was observed (SIR 1.7, 95% CI 0.3-4.9). CONCLUSIONS: Despite an increase in the occurrence of cervical cancer precursors, no increase in the risk of cervical cancer was found in a population of HIV-infected women who receive treatment for their infection and have access to ICC prevention services.

Semen quality of young men in Switzerland: a nationwide cross-sectional population-based study.

BACKGROUND: Sperm counts have been steadily decreasing over the past five decades with regional differences in the Western world. The reasons behind these trends are complex, but numerous insights indicate that environmental and lifestyle factors are important players. OBJECTIVE: To evaluate semen quality and male reproductive health in Switzerland. MATERIALS AND METHODS: A nationwide cross-sectional study was conducted on 2523 young men coming from all regions of Switzerland, recruited during military conscription. Semen volume, sperm concentration, motility, and morphology were analyzed. Anatomy of the genital area and testicular volume was recorded. Testicular cancer incidence rates in the general population were retrieved from Swiss regional registries. RESULTS: Median sperm concentration adjusted for period of sexual abstinence was 48 million/mL. Comparing with the 5th percentile of the WHO reference values for fertile men, 17% of men had sperm concentration below 15 million/mL, 25% had less than 40% motile spermatozoa, and 43% had less than 4% normal forms. Disparities in semen quality among geographic regions, urbanization rates, and linguistic areas were limited. A larger proportion of men with poor semen quality had been exposed in utero to maternal smoking. Furthermore, testicular cancer incidence rates in the Swiss general population increased significantly between 1980 and 2014. DISCUSSION: For the first time, a systematic sampling among young men has confirmed that semen quality is affected on a national level. The median sperm concentration measured is among the lowest observed in Europe. No specific geographical differences could be identified. Further studies are needed to determine to what extent the fertility of Swiss men is compromised and to evaluate the impact of environmental and lifestyle factors. CONCLUSION: A significant proportion of Swiss young men display suboptimal semen quality with only 38% having sperm concentration, motility, and morphology values that met WHO semen reference criteria.

[Environmental pollutants and prostate cancer: epidemiological data]. / Polluants environnementaux et cancer de la prostate: données épidémiologiques.

Prostate cancer is the most frequent cancer affecting men in most Western countries. Certain risk factors have been identified (age, family history, ethnic origin), but the aetiology of this cancer remains largely unknown. However, a role for environmental factors is strongly suspected. Questions have been raised concerning the role of the chemical substances generated by human activities in the occurrence of this disease. Diverse studies have consistently demonstrated a higher risk of prostate cancer in agricultural populations than in the general population. The hypothesis that this higher risk is linked to the use of pesticides has been tested in a number of studies, mostly in North America and Europe. However, to date, with a few possible exceptions, it has been impossible to demonstrate a significant association between exposure to pesticides or a chemical family of pesticides and prostate cancer. Studies have also been carried out on the role of exposure to trace metals, such as cadmium, or to pollutants from industry, such as polychlorobiphenyls. However, no firm conclusions have been drawn. Finally, the effect of chemical substances with endocrine disruptor activity on the occurrence of prostate cancer remains largely unexplored in epidemiological studies. In the face of these uncertainties, rigorous studies are required, with objective measurements of exposure, taking into account confounding factors and individual risk factors, making it possible to assess gene-environment interactions.

Glycol ethers and semen quality: a cross-sectional study among male workers in the Paris Municipality.

OBJECTIVES: Apparent increases in human male reproductive disorders, including low sperm production, may have occurred because of increased chemical exposure. Various glycol ether-based solvents have pronounced adverse effects on sperm production and male fertility in laboratory animals. The authors investigated the effects of past and current exposure to glycol ether-containing products on semen quality and reproductive hormones among men employed by the Paris Municipality. METHODS: Between 2000 and 2001 the authors recruited 109 men who gave semen, blood and urine samples and underwent an andrological examination. Information on lifestyle, occupation, exposure and medical history was obtained by interview. According to their job and chemical products used during the period 1990-2000, men were classified as either occupationally exposed or non-exposed. Current exposure levels to glycol ethers at the time of the study were evaluated by biological monitoring of six urinary metabolites. RESULTS: Previous exposure to glycol ethers was associated with an increased risk for sperm concentration, for rapid progressive motility and for morphologically normal sperm below the World Health Organization semen reference values. No effect of previous glycol ether exposure on hormones levels was observed. By contrast, current glycol ether exposure levels were low and not correlated with either seminal quality or hormone levels. CONCLUSIONS: This study suggests that most glycol ethers currently used do not impact on human semen characteristics. Those that were more prevalent from the 1960s until recently may have long lasting negative effects on human semen quality.

Implication of a tyrosine residue in the unspecific bile salt binding site of human pancreatic carboxylic ester hydrolase.

Tyrosine residues of the human pancreatic carboxylic-ester hydrolase (EC 3.1.1.1) (also referred to as cholesterol-ester hydrolase, EC 3.1.1.13) were nitrated in the ortho-position by the use of tetranitromethane. The specificity of the reaction has been verified and the inhibition observed was shown to be unrelated to the weak polymerization of the protein. Among the 27 tyrosines present in the enzyme, seven or eight were nitrated but only one residue, with a pK of 8.3, seems to be responsible for the loss of activity. This decrease in enzyme activity appears only in assays which were performed in the presence of bile salts, suggesting that of the two bile salt binding sites postulated on the enzyme, only one, referred to the as the 'unspecific site' (Lombardo, D. and Guy, O. (1980) Biochim. Act 611, 147-155), was modified. This is in agreement with the similar loss of enzyme activity observed on emulsified and soluble substrate. The most important result is the difference observed in experiments of the protective effects of bile salts. The protection with sodium taurodeoxycholate is independent of its critical micellar concentration, showing that monomers protect this site, whereas the protection observed in experiments with sodium cholate appears only for supramicellar concentrations of bile salt. Since this latter bile salt promotes the dimerization of the enzyme, we can conclude that a premicellar bile salt binding site (protected by monomers) is transformed in a functional micellar binding site (protected by micelles). This conformational transformation seems to be consecutive to the dimerization, as has been recently proposed.

The INSERM expert review on glycol ethers: findings and recommendations.

The use of glycol ethers and their effects on health have recently attracted the attention of the French health authorities. At their request, INSERM, the French Institute of Health and Medical Research, conducted a collective expertise review on glycol ethers in 1999. INSERM Expertise Reviews are independent procedures performed by experts from several disciplines, to guarantee the objectivity and the relevance of the report. During several work sessions, the experts carried out a critical analysis of and reviewed studies concerning the toxicity of glycol ethers. This process resulted in a series of recommendations and conclusions. All these data have been published in the form of a report and have been used to help the public authorities to make decisions on how to prevent risks for professionals and consumers.

The human pancreatic stone protein.

Chronic calcifying pancreatitis (CCP) is characterized by the presence of stones in pancreatic ducts. Calcium carbonate (CaCO3) is the main constituent of stones, to which is associated an organic matrix consisting primarily of one protein of Mr 14,000, the pancreatic stone protein or PSP. PSP is not present as such in pancreatic juice, but in polymorphic forms with higher molecular weights. These secretory forms (PSP S2-5, Mr 16-19,000) are synthesized in the acinar cells of the pancreas and secreted along the same secretory pathway as the exocrine enzymes. The heterogeneity of the forms of higher Mr (PSP S2-5) is probably due to different glycosylation patterns. PSP and PSP S1 are generated by the cleavage of an Arg-Ile bond in the N-terminal part of PSP S2-5. The N-terminal sequence of PSP (40 amino acids) is identical to that of PSP S1, whose complete sequence (133 amino acids) has been determined. Yet, the two proteins differ by their pI. Pancreatic juice is normally supersaturated in CaCO3, suggesting the presence of a stabilizer preventing CaCO3 precipitation. The PSP S could play that role, since an activity inhibiting the nucleation and growth in vitro of CaCO3 crystals was found in pancreatic juice, associated with these proteins. Moreover, PSP S concentration was significantly lower in the pancreatic juice of patients with CCP than in control patients. Proteins homologous to PSP S were also found in the dog, rat, swine, monkey and ox. They constitute a new family of pancreatic secretory proteins, whose biological role would be to maintain pancreatic juice in a stable state towards CaCO3.

Monoclonal antibodies to pancreatic stone protein. Radioimmunoassay and immunological comparison with trypsin 1.

Monoclonal antibodies were prepared against pancreatic stone protein, a protein which inhibits calcium carbonate precipitation. Two monoclonal antibodies designated D4 and 2E7 were characterized. Immunoadsorbant columns, obtained by linkage of these monoclonal antibodies to Affigel 10, have been used to isolate immunoreactive forms of pancreatic stone protein from nonactivated human pancreatic juice. These monoclonal antibodies permitted us to test the possible immunological relationship between pancreatic stone protein and human trypsin 1. No immunological similarity was found, in agreement with our previous results, and it was established that pancreatic stone protein is a novel protein and not a degradation product of human trypsin(ogen) 1.