Prenatal exposure to airborne polychlorinated biphenyl congeners and male reproductive health.

STUDY QUESTION: Is fetal exposure to lower-chlorinated polychlorinated biphenyls (LC-PCBs) in indoor air of private homes built with PCB-containing materials associated with semen characteristics and testicular volume in adult men? SUMMARY ANSWER: We observed only marginal and inconsistent associations between maternal exposure to PCBs in indoor air and semen quality, testicular size and reproductive hormones in the adult offspring. WHAT IS KNOWN ALREADY: Recent studies have shown LC-PCBs to exhibit endocrine-disrupting properties and increase the risk of cryptorchidism. Although exposure to LC-PCBs in indoor air is relatively common, the long-term impact of prenatal exposure on male reproductive health has not yet been investigated. STUDY DESIGN, SIZE, DURATION: In this cohort study, participants were men (18+ years) whose mothers carried them while living in one of two residential areas where indoor air had been contaminated by LC-PCB evaporating from building materials in subsets of the apartments. Men were considered prenatally exposed if their mother had lived in a PCB-contaminated apartment and unexposed if their mother had lived in an uncontaminated apartment for a minimum of 1 year during the 3.6 years before conception or during the first trimester. Mothers of prenatally unexposed men could not have lived in a contaminated apartment at any point. Recruitment lasted from 2017 to 2019. In total, 73 exposed and 111 unexposed men gave a blood and semen sample. PARTICIPANTS/MATERIALS, SETTING, METHODS: Percentage differences in semen volume, sperm concentration, total sperm count, morphologically normal spermatozoa, progressively motile spermatozoa and DNA fragmentation index (DFI) between prenatally exposed and unexposed men were estimated using negative binomial regression. Associations with total and calculated free testosterone (CFT), LH and FSH were modeled using the linear regression. Odds of small testicular volume was estimated with logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, the results of this study were conflicting. No differences in semen volume, sperm concentration, testosterone and CFT were observed between the groups, but there were slight indications of lower total sperm count, increased FSH and risk of small testicles, alongside lower sperm DFI and a higher proportion of normal spermatozoa in men exposed to LCB-PCBs from indoor air during fetal life. There is no apparent biologically plausible explanation for the apparently improved measures of DNA fragmentation and morphology, and these findings may have occurred purely by chance. LIMITATIONS, REASONS FOR CAUTION: Owing to the indirect measure of exposure, lack of adjustment for paternal factors, the potential for self-selection due to known exposure status and fertility issues, inability to take time spent away from the residence, limited statistical power and lack of comparable literature, independent replication of the study in larger cohorts is warranted. WIDER IMPLICATIONS OF THE FINDINGS: While our findings may appear reassuring for the large number of people residing and/or working in buildings with indoor air contaminated with LC-PCBs, further efforts to understand the full range of health consequences of fetal LC-PCB exposure are needed. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Independent Research Fund Denmark (ref no. 6110-00085B), Bispebjerg Hospital, Landsbyggefonden, Realdania (ref. no. PRJ-2017-00176), Grundejernes Investeringsfond (ref. no. 18-58) and Helsefonden (ref. no. 16-B-01-22 and 21-B-0412). K.S.H. was supported by FFIKA, Focused Research Effort on Chemicals in the Working Environment, from the Danish Government. The authors declare that they have no financial, personal or professional competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Birth weight for gestational age and the risk of infertility: a Danish cohort study.

STUDY QUESTION: Is birth weight for gestational age associated with infertility in adulthood among men and women? SUMMARY ANSWER: Being born small for gestational age (SGA) was associated with infertility in adulthood among men. WHAT IS KNOWN ALREADY: Fetal growth restriction may affect fertility, but results from previous studies have been inconsistent. STUDY DESIGN, SIZE, DURATION: In this population-based cohort study, we used data from a Danish birth cohort, including 5594 men and 5342 women born between 1984 and 1987. Information on infertility was obtained from Danish health registers during the period from the participants' 18th birthday and up until 31 December 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were men and women born in two Danish municipalities, Aalborg and Odense. Information on birth weight and gestational age was obtained from birth records, and information on infertility diagnoses and fertility treatment was retrieved from the Danish National Patient Registry (NPR) and the Danish In Vitro Fertilisation (IVF) registry. Information on potential maternal confounders was obtained from questionnaires during pregnancy and was included in adjusted analyses. Logistic regression analysis was used to estimate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for infertility according to birth weight for gestational age. MAIN RESULTS AND THE ROLE OF CHANCE: Men born SGA had a 55% higher risk of being diagnosed with or treated for infertility compared to men born appropriate for gestational age (AGA) (adjusted OR = 1.55, 95% CI: 1.09-2.21). The association attenuated after exclusion of men born with hypospadias or cryptorchidism (OR = 1.37, 95% CI: 0.93-2.01). No association was found between women's birth weight for gestational age and risk of infertility (adjusted OR = 1.00, 95% CI: 0.73-1.37). LIMITATIONS, REASONS FOR CAUTION: Estimation of gestational age is associated with some uncertainty and might have caused non-differential misclassification. The study design implicitly assumed similar distribution of reproductive and health-seeking behaviour across the groups that were compared. WIDER IMPLICATIONS OF THE FINDINGS: Men born SGA had a higher risk of infertility. Genital malformations may account for part of the observed association, but this must be explored further. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Health, Aarhus University. No competing interests are declared. TRIAL REGISTRATION NUMBER: N/A.

Chronic maternal inflammation or high-fat-feeding programs offspring obesity in a sex-dependent manner.

BACKGROUND/OBJECTIVES: The current world-wide obesity epidemic partially results from a vicious circle whereby maternal obesity during pregnancy predisposes the offspring for accelerated weight gain and development of metabolic syndrome. Here we investigate whether low-grade inflammation, characteristic of the obese state, provides a causal role for this disastrous fetal programming in mice. METHODS: We exposed pregnant and lactating C57BL/6JBom female mice to either high-fat diet (HFD), or continuous infusion of lipopolysaccharide (LPS), a potent trigger of innate immunity, and studied offspring phenotypes. RESULTS: Both maternal LPS or HFD treatments rendered the offspring hyperphagic and inept of coping with a HFD challenge during adulthood, increasing their adiposity and weight gain. The metabolic effects were more pronounced in female offspring, while exposed male offspring mounted a larger inflammatory response to HFD at adulthood. CONCLUSIONS: This supports our hypothesis and highlights the programming potential of inflammation in obese pregnancies.

Airway exposure to multi-walled carbon nanotubes disrupts the female reproductive cycle without affecting pregnancy outcomes in mice.

BACKGROUND: The use of multiwalled carbon nanotubes (MWCNT) is increasing due to a growing use in a variety of products across several industries. Thus, occupational exposure is also of increasing concern, particularly since airway exposure to MWCNTs can induce sustained pulmonary acute phase response and inflammation in experimental animals, which may affect female reproduction. This proof-of-principle study therefore aimed to investigate if lung exposure by intratracheal instillation of the MWCNT NM-400 would affect the estrous cycle and reproductive function in female mice. RESULTS: Estrous cycle regularity was investigated by comparing vaginal smears before and after exposure to 67 µg of NM-400, whereas reproductive function was analyzed by measuring time to delivery of litters after instillation of 2, 18 or 67 µg of NM-400. Compared to normal estrous cycling determined prior to exposure, exposure to MWCNT significantly prolonged the estrous cycle during which exposure took place, but significantly shortened the estrous cycle immediately after the exposed cycle. No consistent effects were seen on time to delivery of litter or other gestational or litter parameters, such as litter size, sex ratio, implantations and implantation loss. CONCLUSION: Lung exposure to MWCNT interfered with estrous cycling. Effects caused by MWCNTs depended on the time of exposure: the estrous stage was particularly sensitive to exposure, as animals exposed during this stage showed a higher incidence of irregular cycling after exposure. Our data indicates that MWCNT exposure may interfere with events leading to ovulation.

Prenatal maternal stress and atopic diseases in the child: a systematic review of observational human studies.

BACKGROUND: A growing number of studies suggest that maternal stress during pregnancy promotes atopic disorders in the offspring. This is the first systematic review to address prenatal maternal stress (PNMS) and the subsequent risk of atopy-related outcomes in the child. METHODS: The review was performed in accordance to the PRISMA criteria. We searched and selected studies in PubMed, Scopus, Embase and PsychINFO until November 2014. RESULTS: Sixteen (with 25 analyses) of 426 identified articles met the review criteria. Five main PNMS exposures (negative life events, anxiety/depression, bereavement, distress and job strain) and five main atopic outcomes (asthma, wheeze, atopic dermatitis, allergic rhinitis and IgE) were assessed across the studies. Overall, 21 of the 25 analyses suggested a positive association between PNMS and atopic outcomes. Of the 11 exposure-response analyses reported, six found statistically significant trends. CONCLUSION: This systematic review suggests a relationship between maternal stress during pregnancy and atopic disorders in the child. However, the existing studies are of diverse quality. The wide definitions of often self-reported stress exposures imply a substantial risk for information bias and false-positive results. Research comparing objective and subjective measures of PNMS exposure as well as objective measures for atopic outcome is needed.

Psychosocial job strain and risk of congenital malformations in offspring--a Danish National cohort study.

OBJECTIVE: To investigate if maternal exposure to psychosocial job strain at work (high demands and low control) measured by questionnaire early in pregnancy (median week 15) is associated with malformations in the offspring. DESIGN: Population-based cohort study. SETTING: The Danish National Birth Cohort. POPULATION: A cohort of 60,386 singleton children with full information on mother's occupational status, exposure to psychosocial job strain and all covariates during pregnancy. METHODS: Logistic regression analysis was used to calculate the odds of congenital malformations as a function of job strain with adjustment for maternal age, body mass index, parity, smoking, alcohol use, manual versus nonmanual work, maternal serious disease and gestational age at interview. MAIN OUTCOME MEASURES: Circulatory malformation, musculoskeletal malformation or any malformation. RESULTS: Logistic regression analyses, both crude and adjusted, indicated no associations between working under high strain and giving birth to a child with circulatory malformation (adjusted odds ratio [OR] 1.04, 95% confidence interval [95% CI] 0.75-1.44), musculoskeletal malformation (aOR 0.88, 95% CI 0.71-1.10) or any malformation (aOR 0.99, 95% CI 0.85-1.15). Supplementary analyses including restriction to first-borns and a stratified analysis with respect to manual and nonmanual work did not change the results. CONCLUSIONS: Association between exposure to high job strain during pregnancy and elevated risk of circulatory, muscle and any malformations is not supported by this study.

Risk assessment of consumer spray products using in vitro lung surfactant function inhibition, exposure modelling and chemical analysis.

Consumer spray products release aerosols that can potentially be inhaled and reach the deep parts of the lungs. A thin layer of liquid, containing a mixture of proteins and lipids known as lung surfactant, coats the alveoli. Inhibition of lung surfactant function can lead to acute loss of lung function. We focused on two groups of spray products; 8 cleaning and 13 impregnation products, and in the context of risk assessment, used an in vitro method for assessing inhibition of lung surfactant function. Original spray-cans were used to generate aerosols to measure aerodynamic particle size distribution. We recreated a real-life exposure scenario to estimate the alveolar deposited dose. Most impregnation products inhibited lung surfactant function at the lowest aerosolization rate, whereas only two cleaning products inhibited function at the highest rates. We used inhibitory dose and estimated alveolar deposition to calculate the margin of safety (MoS). The MoS for the inhibitory products was ≤1 for the impregnation products, while much larger for the cleaning products (>880). This risk assessment focused on the risk of lung surfactant function disruption and provides knowledge on an endpoint of lung toxicity that is not investigated by the currently available OECD test guidelines.

In vitro prediction of clinical signs of respiratory toxicity in rats following inhalation exposure.

To date there are no OECD validated alternative approaches to study toxicity following inhalation exposure to airborne chemicals. The available OECD test guidelines for acute inhalation toxicity aim to estimate a value of the lethal air concentration of the test chemical leading to the death of 50% of the exposed animals (LC50), to satisfy hazard classification and labelling requirements. This paper explores the view that alternative approaches must compare to outcomes of existing guideline methods to become accepted and implemented in a regulatory context. This case study describes the initiatives taken to validate the lung surfactant bioassay, an in vitro cell-free method, and discusses the challenges faced. While the lung surfactant bioassay could not predict the GHS classification for acute inhalation toxicity of 26 chemicals, the assay successfully predicted the clinical signs of respiratory toxicity observed during or shortly after exposure in vivo as reported in registration dossiers. The lung surfactant bioassay is a promising alternative approach to assess the potential of chemicals to cause changes to respiration remaining after exposure (indicating decreased lung function), and can be combined with other test methods in an integrated approach to testing and assessment of inhaled substances.

Reduced mobility but unaffected startle response in female rats exposed to prenatal dexamethasone: different sides to a phenotype.

An adverse fetal environment is strongly associated with behavioral and emotional development in later life, and environmental interactions with the genome are essential in the development of pathophysiology. This implicates that a genetic vulnerability or other predisposition may interact with the environment and stressful life events to trigger mental disease. The startle reflex is highly sensitive to fear and anxiety in humans and animals. Elevated startle magnitude has been proposed as a marker for neurodevelopmental disorders. We have recently established an animal model for possible development of anxiety, where female rats are exposed to two stressful life events, during prenatal life and as adolescents, respectively. A blood sampling procedure 3 months prior to startle testing has previously been found to increase basal startle, but only in prenatally stressed rats. As the experimental procedure of acoustic startle response (ASR) measurement resembles the aversive blood sampling procedure, this suggests that effects on ASR may be caused by aversive contextual similarities between blood sampling under restraint and the ASR test. In the present study, postnatal blood sampling was replaced by another dissimilar stressful event. Animals exposed to a high prenatal glucocorticoid level (i.e. 150 mug dexamethasone/kg) were statistically significantly more immobile in the forced swim test (FST) than animals exposed to a lower level of dexamethasone (50 mug/kg) and control animals. Exposure to a novel contextual stressor at 3 months of age (FST) was unassociated with changes in basal startle. These data suggest, since the high prenatal dexamethasone group showed increased immobility in the FST but coped equally well with controls in the ASR, that the outcome of environmental influences is determined by the individual circumstances as different situations require different coping abilities in the same individual.

Regional cerebral blood flow in focal cortical epilepsy.

Regional cerebral blood flow (rCBF) was studied in ten patients with focal cortical epilepsy. The blood flow was measured by the intra-arterial injection of xenon 133 (133Xe), and the isotope clearance was recorded by a multidetector scintillation camera with 254 detectors. Three patients were studied both during a seizure and (in the same setting) in the interictal period; six patients were studied only in the interictal period, and one patient was studied only during a seizure. Studies during seizures all showed marked flow increases in areas presumed to participate in the seizure activity. This finding accords with earlier studies. All nine patients studied in the interictal phase showed, either spontaneously or during activation by intermittent light, focal flow increases in areas presumed to comprise the epileptic focus. These interictal hyperemic foci probably reflect subictal neuronal hyperactivity in epileptogenic nervous tissue. Only two of the patients had distinct epileptic electroencephalographic foci. It appears that rCBF studies can be a valuable diagnostic tool in the investigation of cortical epileptogenic lesions.

Casual blood pressure in a general Danish population. Relation to age, sex, weight, height, diabetes, serum lipids and consumption of coffee, tobacco and alcohol.

A population survey was conducted on 3608 randomly selected Danes aged 30, 40, 50 and 60 years respectively. Of these, 3400 were not in medical treatment for arterial hypertension. The following parameters were investigated: sex, age, serum lipid levels (total cholesterol, HDL cholesterol, triglycerides), presence of diabetes mellitus, height, body mass index (BMI), and average daily consumption of coffee, tobacco and alcohol. Analysis with multiple linear regression showed that all variables with the exception of triglycerides, HDL cholesterol and height were significantly associated with systolic blood pressure. Likewise all factors except diabetes, triglycerides and height were significantly associated with diastolic blood pressure. Further analysis in which the effect of each parameter was corrected for by the effects of the remaining variables, demonstrated that apart from age and sex only BMI and high alcohol consumption were positively associated with differences in blood pressure greater than a few mmHg. However, the variation in both systolic and diastolic blood pressures was only partly accounted for by the parameters studied--in the covariates analysis R2 for systolic blood pressure was 0.28 and R2 for diastolic blood pressure was 0.30. In conclusion, this investigation demonstrated that blood pressure is relatively independent of other factors important in the development of cardiovascular disease. Of the above-mentioned factors with some influence on blood pressure only age, BMI and high alcohol consumption have potential clinical importance.

Traumatic posterior fracture-dislocation of the hip with fracture of the femoral head or neck, or both.

To determine the prognosis and best treatment for patients who have a posterior dislocation of the hip associated with a fracture of the femoral head or neck (Grade IV, according to the classification of Stewart and Milford), we surveyed the records of 201 patients who had been treated for 203 posterior dislocations from 1958 to 1985 and selected the cases of 19 patients (19 posterior fracture-dislocations of the hip) for further review. Each of the injuries had resulted from a motor-vehicle accident. Thirteen patients had had a posterior dislocation with an associated fracture of the femoral head located either caudad or cephalad to the fovea centralis (Pipkin Type-I or Type-II injury), one had had a posterior dislocation with associated fractures of the femoral head and neck (Pipkin Type III), two had had a posterior dislocation with associated fractures of the femoral head and the acetabular rim (Pipkin Type IV), and three had had a fracture-dislocation that we could not categorize according to the Pipkin classification. Twelve patients had been treated by closed reduction for a Type-I or Type-II injury; one, by open reduction after an unsuccessful closed reduction for a Type-I injury; one, by primary total hip replacement for a Type-III injury; and three, by open reduction with screw fixation of the acetabular fracture and removal of the fragment of the head for two Type-IV injuries and one unclassified injury. An additional two patients had had both a fracture of the femoral neck and a dislocation; one hip was treated primarily with a Moore prosthesis and the other was left unreduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Coxarthrosis following traumatic posterior dislocation of the hip.

One hundred and twenty-seven hips in 125 adults were treated for traumatic posterior dislocation during a period of two decades. Ninety-eight patients (100 hips) were available for follow-up examination at a minimum of five years (average, fourteen years) after injury. By both clinical and radiographic criteria eighty hips (80 per cent) had an excellent or good result. Forty-two per cent of the hips that were reduced more than six hours after the dislocation had an excellent or good result and 88 per cent of those that were reduced within six hours after dislocation had an excellent or good result. Thirty-one per cent of the hips with a Grade-III dislocation had an excellent or good result, as compared with 90 per cent of those with a Grade-I dislocation. Twenty-two per cent of the hips with an excellent or good result had avascular necrosis of the femoral head. We found the time-interval between injury and reduction, the severity of the initial injury, and the development of avascular necrosis of the femoral head to be the most important factors with regard to the long-term prognosis. Avascular necrosis occurred most frequently in hips that underwent reduction after a delay of more than six hours.

Sleep apnea syndrome--an alternative treatment to tracheostomy.

Two patients with obstructive sleep apnea syndrome had polygraphic recordings demonstrated upper airway obstruction and sleep with extremely short sleep latency, severely disturbed nightsleep resulting in sleep deprivation, and excessive daytime sleepiness. Radiological investigation showed the upper airway obstruction to be caused by the tongue falling back occluding the pharynx. Nasopharyngeal intubation relieved the symptoms. The patients were trained to perform this treatment themselves every night, demonstrating that this treatment is an attractive alternative to the conventional tracheotomy.

Effects of prenatal exposure to toluene on postnatal development and behavior in rats.

Development and neurobehavioral effects of prenatal exposure to toluene (CAS 108-88-3) were studied after exposing pregnant rats (Mol:WIST) to 1800 ppm of the solvent for 6 h daily on days 7-20 of gestation. Body weights of exposed offspring were lower until day 10 after parturition. Neurobehavioral evaluation of the pups revealed no effects on motor function (rotarod), activity level (open field), acoustic startle, and prepulse inhibition. Measurements of hearing function using auditory brain stem response revealed small effects in male-exposed offspring. Performance in a Morris water maze during initial learning gave some indications of impaired cognitive functions, which was confirmed during further testing, especially in reversal and new learning. Effects on cognitive functions seemed most marked in female offspring.

Developmental neurotoxicity after toluene inhalation exposure in rats.

Rats were exposed to 1200 ppm or 0 ppm toluene (CAS 108-88-3) for 6 h per day from day 7 of pregnancy until day 18 postnatally. Developmental and neurobehavioral effects in the offspring were investigated using a test battery including assessment of functions similar to those in the proposed OECD TG for Developmental Neurotoxicity Study, i.e., physical development, reflex ontogeny, motor function, motor activity, sensory function, and learning and memory. The exposure did not cause maternal toxicity or decreased viability of the offspring. Lower birth weight, delayed ontogeny of reflexes, and increased motor activity in the open field was registered in the exposed offspring. Impaired cognitive function was revealed in the exposed female offspring at the age of 3.5 months, i.e., they used more time to locate the hidden platform in the Morris water maze after platform relocation. The difference was not related to poorer swimming capabilities, because swim speeds were similar to control values. The results show that exposure to 1200 ppm toluene during brain development caused long-lasting developmental neurotoxicity in rats.

Computerised tomography after posterior dislocation of the hip.

We have reviewed 19 consecutive patients admitted to the Odense University Hospital after traumatic dislocation of the hip. We aimed to perform computerised tomography as soon as possible after closed reduction; this was accomplished in 15 patients. The CT scans revealed intra-articular fragments of bone in five hips, and fractures of the femoral head or acetabulum in six. In two cases the CT scans excluded fractures or intra-articular fragments which had been suspected on conventional radiography. CT scanning is a useful diagnostic tool in traumatic dislocation of the hip; we consider that it makes an important contribution to management.

Effects of R-(+)- and S-(-)-limonene on the respiratory tract in mice.

The effects of airborne R-(+)- and S-(-)- limonene were studied in conscious BALB/c mice by continuous monitoring respiratory rate (f), tidal volume (VT) and mid-expiratory flow rate (VD) during an exposure period of 30 min. Both enantiomers decreasedf from a trigeminal reflex, i.e., due to sensory irritation. The exposure concentration decreasing f by 50% (RD50) in the first 10 min of the exposure period was estimated to be 1,076 ppm for R-(+)-limonene and 1,467 ppm for S-(-)-limonene. Results for sensory irritation of R-(+)-limonene in BALB/c mice and humans are in close agreement. The reported sensory irritation threshold is above 80 ppm in humans while the no-observed-effect level was estimated to be 100 ppm in mice. The enantiomers were devoid of pulmonary irritation or general anesthetic effects with R-(+)-limonene < or =1,599 ppm and S-(-)-limonene < or =2,421 ppm. R-(+)-limonene did not influence VT below 629 ppm. S-(-)-limonene increased VT above 1,900 ppm. Both enantiomers induced a mild bronchoconstrictive effect above 1,000 ppm.

Acute airway effects of formaldehyde and ozone in BALB/c mice.

1. Concentration and time-effect relationships of formaldehyde and ozone on the airways were investigated in BALB/c mice. The effects were obtained by continuous monitoring of the respiratory rate, tidal volume, expiratory flow rate, time of inspiration, time of expiration, and respiratory patterns. 2. With concentrations up to 4 p.p.m., formaldehyde showed mainly sensory irritation effects of the upper airways that decrease the respiratory rate from a trigeminal reflex. The no-effect level (NOEL) was about 0.3 p.p.m. This value is close to the human NOEL, which is about 0.08 p.p.m. 3. Ozone caused rapid, shallow breathing in BALB/c mice. Later on, the respiratory rate decreased due to another vagal response that indicated an incipient lung oedema. The NOEL in mice was about 1 p.p.m. during 30 min of ozone exposure. No major effect occurs in resting humans at about 0.4 p.p.m. 4. Thus, the upper airway irritant, formaldehyde, and the deep lung irritant, ozone, showed the same types of respiratory effects in humans and in BALB/c mice. Also, the sensitivity was nearly identical. Continuous monitoring of respiratory effects in BALB/c mice, therefore, may be a valuable method for the study of effects of other environmental pollutants, which, however, should be confirmed in further studies.