Perinatal exposure to potential endocrine disrupting chemicals and autism spectrum disorder: From Norwegian birth cohort to zebrafish studies.

BACKGROUND: The etiology of autism spectrum disorder (ASD) is multifactorial, involving genetic and environmental contributors such as endocrine-disrupting chemicals (EDCs). OBJECTIVE: To evaluate the association between perinatal exposure to 27 potential EDCs and ASD among Norwegian children, and to further examine the neurodevelopmental toxicity of associated chemicals using zebrafish embryos and larvae. METHOD: 1,199 mothers enrolled in the prospective birth-cohort (HUMIS, 2002-2009) study. Breastmilk levels of 27 chemicals were measured: polychlorinated biphenyls, organochlorine pesticides, polybrominated diphenyl ethers, and perfluoroalkyl substances as a proxy for perinatal exposure. We employed multivariable logistic regression to determine association, utilized elastic net logistic regression as variable selection method, and conducted an in vivo study with zebrafish larvae to confirm the neurodevelopmental effect. RESULTS: A total of 20 children had specialist confirmed diagnosis of autism among 1,199 mother-child pairs in this study. ß-Hexachlorocyclohexane (ß-HCH) was the only chemical associated with ASD, after adjusting for 26 other chemicals. Mothers with the highest levels of ß-HCH in their milk had a significant increased risk of having a child with ASD (OR = 1.82, 95 % CI: 1.20, 2.77 for an interquartile range increase in ln-transformed ß-HCH concentration). The median concentration of ß-HCH in breast milk was 4.37 ng/g lipid (interquartile range: 2.92-6.47), and the estimated daily intake (EDI) for Norwegian children through breastfeeding was 0.03 µg/kg of body weight. The neurodevelopmental and social behavioral effects of ß-HCH were established in zebrafish embryos and larvae across various concentrations, with further analysis suggesting that perturbation of dopaminergic neuron development may underlie the neurotoxicity associated with ß-HCH. CONCLUSIONS: Prenatal exposure to ß-HCH was associated with an increased risk of specialist-confirmed diagnoses of ASD among Norwegian children, and the EDI surpasses the established threshold. Zebrafish experiments confirm ß-HCH neurotoxicity, suggesting dopaminergic neuron disruption as a potential underlying mechanism.

Aryl hydrocarbon receptor activity in human breast milk and cryptorchidism: A case-control study within the prospective Norwegian HUMIS cohort.

BACKGROUND: The etiology of cryptorchidism remains poorly understood. Endocrine disrupting chemicals can impact estrogen signaling by interacting with aryl hydrocarbon receptor (AhR) activity. OBJECTIVE: To evaluate whether AhR activity in breast milk samples is associated with cryptorchidism. METHOD: We conducted a case-control study based on 199 mother-child pairs (n = 91 cases/108 controls) selected from the Norwegian Human Milk Study (2002-2009). We defined cases for cryptorchidism based on maternal reports at 1-, 6-, 12-, and 24- months after birth. Chemically- and biologically stable AhR activity (pg 2,3,7,8-TCDD equivalent (TEQ)/g lipid) was determined by DR- CALUX® assay in the mothers' milk collected at a median of 33 (10th-90th percentile: 18-57) days after delivery. We used multivariate logistic regression to compare AhR activity levels between cases and controls, and linear regression separately, to establish the relationship with the presence of 27 potential EDCs measured in breast milk and AhR activity. RESULTS: The average estimated daily intake (EDI) of dioxin and (dioxin-like (dl)-compounds via breast milk is 33.7 ± 17.9 pg TEQ/kg bodyweight per day among Norwegian children. There were no significant differences in AhR activation in breast milk samples between cases with cryptorchidism and controls. Among the 27 chemicals measured in breast milk, AhR activity was (borderline) significantly associated with all dl-PCBs, three non-dioxin-like (ndl)-PCBs (PCB-74, PCB-180, PCB-194) and two organochlorine pesticides (OCPs; HCB, ß-HCH). No associations between AhR activity and brominated flame retardants (PBDEs) or poly- and perfluoroalkyl substances (PFASs). CONCLUSION: No association between AhR activity and cryptorchidism was found among Norwegian boys. The average EDI of dioxin and dl-compounds in exclusively breastfed Norwegian infants remains above the safety threshold and, therefore requires further reduction measures. Consistent with a possible role in the observed AhR activity, all dl-PCBs were associated with AhR activity whereas the association was null for either PBDEs or PFASs.

A case-cohort study of perinatal exposure to potential endocrine disrupters and the risk of cryptorchidism in the Norwegian HUMIS study.

BACKGROUND: Exposure to endocrine-disrupting chemicals (EDCs) during the critical period of testicular descent may increase the risk of cryptorchidism and male fertility. OBJECTIVE: To investigate 27 potential EDCs measured in breast milk as a proxy for perinatal exposure and the risk of cryptorchidism in a prospective cohort. METHOD: The Norwegian Human Milk Study (2002-2009) enrolled 2606 mother-infant pairs, of which 1326 were mother-son pairs. In a case-cohort design, we studied 641 male infants who had 27 EDCs already quantified in milk samples: 5 organochlorine pesticides, 14 polychlorinated biphenyls (PCBs), 6 brominated flame retardants, and 2 poly- and perfluoroalkyl substances. We defined cases of congenital, recurrent, persistent and ever-reported cryptorchidism based on questionnaires mothers completed when children were 1, 6, 12 and 24 months old. Variable selection via elastic net logistic regression identified the best cryptorchidism predictors while multivariable logistic regression models determined their effect estimates. RESULTS: The prevalence of reported congenital cryptorchidism was 6.1%, with half spontaneously descending within six months of birth, after which prevalence stabilized between 2.2 and 2.4%. The ever-reported prevalence of cryptorchidism at 1, 6, 12, or 24 months was 12.2%. Elastic net models identified PCB-74 (OR = 1.31, 95% CI: 1.001-1.703), PCB-114 (OR = 1.36, 95% CI: 1.05-1.77), PCB-194 (OR = 1.28, 95% CI: 1.03-1.53) and ß-HCH (OR = 1.26, 95% CI: 1.03-1.53 (per interquartile range increase in concentration of EDCs) as best predictors of congenital cryptorchidism. No EDCs were selected for either recurrent or persistent cryptorchidism, and only PCB-194 was selected by elastic net for ever-reported cryptorchidism (OR = 1.23, 95% CI: 1.01-1.51), in contrast to unpenalized multivariable logistic regression, where most of the individual congeners of PCBs showed significant associations. CONCLUSION: In the largest multi-pollutant analysis to date considering potential confounding from co-exposure to other chemicals, perinatal exposure to PCB-74, PCB-114, PCB-194 and ß-HCH were associated with increased odds of congenital cryptorchidism. Many PCBs may falsely be associated with cryptorchidism when assessed individually, due to confounding by highly correlated chemicals. Experimental studies are warranted to confirm our findings.

Physiologically based pharmacokinetic modeling of nanoceria systemic distribution in rats suggests dose- and route-dependent biokinetics.

BACKGROUND: Cerium dioxide nanoparticles (nanoceria) are increasingly being used in a variety of products as catalysts, coatings, and polishing agents. Furthermore, their antioxidant properties make nanoceria potential candidates for biomedical applications. To predict and avoid toxicity, information about their biokinetics is essential. A useful tool to explore such associations between exposure and internal target dose is physiologically based pharmacokinetic (PBPK) modeling. The aim of this study was to test the appropriateness of our previously published PBPK model developed for intravenous (IV) administration when applied to various sizes of nanoceria and to exposure routes relevant for humans. METHODS: Experimental biokinetic data on nanoceria (obtained from various exposure routes, sizes, coatings, doses, and tissues sampled) in rats were collected from the literature and also obtained from the researchers. The PBPK model was first calibrated and validated against IV data for 30 nm citrate coated ceria and then recalibrated for 5 nm ceria. Finally, the model was modified and tested against inhalation, intratracheal (IT) instillation, and oral nanoceria data. RESULTS: The PBPK model adequately described nanoceria time courses in various tissues for 5 nm ceria given IV. The time courses of 30 nm ceria were reasonably well predicted for liver and spleen, whereas the biokinetics in other tissues were not well captured. For the inhalation, IT instillation, and oral exposure routes, re-optimization was difficult due to low absorption and, hence, low and variable nanoceria tissue levels. Moreover, the nanoceria properties and exposure conditions varied widely among the inhalation, IT instillation, and oral studies, making it difficult to assess the importance of different factors. CONCLUSION: Overall, our modeling efforts suggest that nanoceria biokinetics depend largely on the exposure route and dose.

Cheating on examinations and its predictors among undergraduate students at Hawassa University College of Medicine and Health Science, Hawassa, Ethiopia.

BACKGROUND: Cheating on examinations in academic institutions is a worldwide issue. When cheating occurs in medical schools, it has serious consequences for human life, social values, and the economy. This study was conducted to determine the prevalence of cheating and identify factors that influence cheating among students of Hawassa University College of medicine and health science. METHODS: A cross sectional study was conducted from May through June 2013. A pre-tested self-administered, structured questionnaire was used to collect self-reported data regarding cheating. Data were entered and analyzed using SPSS version 20. Descriptive statistics were used for data summarization and presentation. Degree of association was measured by Chi Square test, with significance level set at p = 0.05. Bivariate and multivariate logistic regression analyses were used to assess associations. RESULTS: The prevalence of self-reported cheating was found to be 19.8% (95% CI = 17.4-21.9). About 12.1% (95% CI = 10.2-13.9) of students disclosed cheating on the entrance examination. The majority of students (80.1% (95% CI = 77.9-82.3) disclosed that they would not report cheating to invigilators even if they had witnessed cheating. Analysis by multiple regression models showed that students who cheated in high school were more likely to cheat (adjusted OR = 1. 80, 95% CI = 1. 01-3.19) and that cheating was less likely among students who didn't cheat on entrance examinations (adjusted OR = 0. 25, 95% CI = 0. 14-0.45). Dining outside the university cafeteria and receiving pocket money of Birr 300 or more were strongly associated with cheating (adjusted OR = 3.08, 95% CI = 1.54-6.16 and adjusted OR = 1.69 (95% CI = 1.05-2.72), respectively. The odds of cheating among students were significantly higher for those who went to private high school, were substance users, and didn't attend lectures than for those who attended government schools, were not substance abusers, and attended lectures. CONCLUSION: Our findings have important implications for development of an institution's policies on academic integrity. By extension, they affect the policies of high schools. Increased levels of supervision during entrance examination, mandated attendance at lectures, and reduction of substance use are likely to reduce cheating. No significant association was found with background, level of parental education, grade point average, and interest in field of study.

Absenteeism among medical and health science undergraduate students at Hawassa University, Ethiopia.

BACKGROUND: Student absenteeism is a major concern for university education worldwide. This study was conducted to determine the prevalence and causes of absenteeism among undergraduate medical and health sciences students at Hawassa University. METHODS: We conducted a cross-sectional study using a pretested self-administered structured questionnaire from May-June 2013. The primary outcome indicator was self-reported absenteeism from lectures in the semester preceding the study period. The study included all regular undergraduate students who were enrolled in the University for at least one semester. The data was entered and analyzed using SPSS version 20. The association between class absenteeism and socio-demographic and behavioral correlates of absenteeism was determined by bivariate and multivariate analyses. Results were reported as crude odds ratios (COR), adjusted odds ratios (AOR) and 95% confidence intervals (CI). RESULTS: 1200 students consented and filled the questionnaire. Of these students, 43.7% had missed three or more lectures and 14.1% (95% CI = 12.2-16.2) missed more than 8 lectures in the preceding semester. There was a significant association between missing more than 8 lectures and age of students, chosen discipline (medicine), and social drug use. The main reasons reported for missing lectures were preparing for another examination, lack of interest, lecturer's teaching style, and availability of lecture material. CONCLUSION: At Hawassa University College of Medicine and Health Science student habits and teacher performance play a role in absenteeism from lectures. A university culture that promotes discipline and integrity especially among medical and older students discourages social drug use will likely improve motivation and attendance. Training in teaching methodologies to improve the quality and delivery of lectures should also help increase attendance.

Assessment of drug use pattern using WHO prescribing indicators at Hawassa University Teaching and Referral Hospital, south Ethiopia: a cross-sectional study.

BACKGROUND: To promote rational drug use in developing countries, it is important to assess drug use pattern using the World Health Organization (WHO) drug use indicators. The aim of this study was to assess the drug prescription patterns at the Medical Outpatient Pharmacy of Hawassa University Teaching and Referral Hospital, using some of the WHO core drug use indicators. METHODS: A descriptive, quantitative, and cross-sectional survey was conducted to determine the current prescribing practices at Hawassa University Teaching and Referral Hospital. The sample was selected using systematic random sampling. 1290 patient encounters were reviewed retrospectively for a 2-year period from September 2007 to September 2009. Data were collected from prescriptions and Prescription registration books retained in the pharmacy. RESULT: The average number of drugs prescribed per encounter or mean was 1.9 (SD 0.91) with a range between 1 and 4. The percentage of encounters in which an antibiotic or injection was prescribed was 58.1% (n = 749) and 38.1% (n = 491), respectively. The Percentage of drugs prescribed by generic name and from an essential drug list was 98.7% (n=2419) and 96.6% (n=2367), respectively. The most commonly prescribed forms of antibiotics were amoxicillin (16.4%), ampicillin (15%), gentamicin (14.9%) and chloramphenicol (11.6%). On the other hand, the most commonly prescribed injections were ampicillin (21.4%), cloxacillin (13.4%), crystalline penicillin (12.4%), ceftriaxon (9.8%) gentamicin (9.8%), diclofenac (9.4%), chloramphenicol 41 (8.4%) and furosemide 25 (5.1%). CONCLUSION: On the basis of the finding of this study, the prescribing practices for antibiotic and injection shows deviation from the standard recommended by WHO. These two commonly overused and costly forms of drug therapy need to be regulated closely. Drug use evaluation should be done for some of the antibiotics to check whether they were appropriately prescribed or not. On the other hand, polypharmacy, generic prescribing and prescribing from EDL were not found to be a problem in this study. Teaching hospitals have a special responsibility to society to promote rational prescribing by their staff and, through them, the future generations of doctors.