Elevated IGF-1 concentrations in children with low grade glioma: A descriptive analysis in a retrospective national cohort.

Children with low grade glioma (LGG) may present with, or develop, elevated concentrations of insulin-like growth factor 1 (IGF-1). The prevalence, pathophysiology, or its possible clinical effects are poorly understood. Our aim was to evaluate the prevalence of such elevated IGF-1 concentrations and to describe its association with linear growth, body mass index (BMI), pituitary outcome, and tumor behavior in a large retrospective national cohort. From a nationwide retrospective cohort of pediatric brain tumor survivors diagnosed between 2002 and 2012, tumor, treatment, endocrine, and auxological data of children with LGG were collected (n = 358). Prevalence and risk factors for elevated IGF-1 concentrations, as well as the association between having elevated IGF-1 concentrations and receiving tumor treatment, were explored. IGF-1 concentrations had only been measured in 45.5% of cases (n = 163/358). In 18.4% of 163 children with available IGF-1 measurements, IGF-1 concentrations were found elevated. No association was described between having an elevated IGF-1 concentration and tumor behavior or height SDS at last moment of follow-up. Multivariate logistic regression identified posterior pituitary disorder (OR 6.14 95% CI: 2.21-17.09) and BMI SDS at follow-up (OR 1.56 95% CI: 1.09-2.20) to be significantly associated with elevated IGF-1 concentrations. In this retrospective cohort of children with LGG, IGF-1 was found elevated in 18.4% of children with available IGF-1 measurements. Elevated IGF-1 seems to be related to hypothalamic dysfunction worsening over time. Larger prospective cohort studies are needed.

A new era for optic pathway glioma: A developmental brain tumor with life-long health consequences.

Optic pathway and hypothalamic glioma (OPHG) are low-grade brain tumors that arise from any part of the visual pathways frequently involving the hypothalamus. The tumors grow slowly and present with features driven by their precise anatomical site, their age at presentation and the stage of growth and development of the host neural and orbital bony tissues. Up to 50% of optic pathway glioma arise in association with Neurofibromatosis type 1 (NF1), which affects 1 in 3,000 births and is a cancer predisposition syndrome. As low-grade tumors, they almost never transform to malignant glioma yet they can threaten life when they present under two years of age. The main risks are to threaten vision loss by progressive tumor damage to optic pathways; furthermore, invasion of the hypothalamus can lead to diencephalic syndrome in infancy and hypopituitarism later in life. Progressive cognitive and behavioural dysfunction can occur, as part of NF1 syndromic features and in sporadic cases where large bulky tumors compress adjacent structures and disrupt neuro-hypothalamic pathways. Persistently progressive tumors require repeated treatments to attempt to control vision loss, other focal brain injury or endocrine dysfunction. In contrast tumors presenting later in childhood can be seen to spontaneously arrest in growth and subsequently progress after periods of stability. These patterns are influenced by NF status as well as stages of growth and development of host tissues. The past two decades has seen an expansion in our understanding and knowledge of the clinical and scientific features of these tumors, their modes of presentation, the need for careful visual and endocrine assessment. This influences the decision-making surrounding clinical management with surgery, radiotherapy, chemotherapy and most recently, the potential benefit of molecularly targeted drug therapy. This article, based upon the authors' clinical and research experience and the published literature will highlight advances in approach to diagnosis, the established role of vision loss as justification of treatments and the emerging evidence of endocrine and neurological consequences that need to be incorporated into judgements for case selection for therapy or observation. Consideration is given to the current state of biological evidence justifying current trials of new therapies, the genetic studies of the NF1 gene and the potential for new approaches to OPHG detection and treatment. The outstanding health system priorities from the perspective of children, their parents and health system commissioners or insurers are discussed.

Evaluating the efficacy and safety of single-agent etoposide intra-CSF chemotherapy in children and young people with relapsed/refractory central nervous system tumours.

PURPOSE: The aim of the project was to evaluate intra-CSF etoposide administration in a palliative setting for children and young people with relapsed/refractory central nervous system (CNS) tumours, with the primary endpoints being overall survival and progression-free survival time. A safety endpoint was to assess the side effect profile and complications of intra-CSF etoposide. METHODS: Thirty-five patients under the age of 30 years (median age: 5.33 years) were enrolled onto the project. The cross-centre study was a service evaluation, with a data collection spreadsheet designed in Nottingham and completed by both Nottingham and Oxford centres. Data was analysed using SPSS, assessing the overall survival and progression-free survival times, as well as the 6-month and 1-year survival rates. RESULTS: The median overall survival and progression-free survival times were 10.97 and 5.91 months, respectively. The 6-month and 1-year overall survival rates were 67% and 48%, and the progression-free survival rates were 50% and 22%. Age at the start of intra-CSF therapy was significantly associated with overall survival (P = 0.046), with the 6 + age group having improved overall survival. Treatment type was significantly associated with overall survival (P = 0.012), with etoposide intra-CSF treatment being associated with improved overall survival. Treatment duration was significantly associated with both overall survival (P < 0.001) and progression-free survival (P < 0.001). CONCLUSION: Intra-CSF etoposide treatment has shown to increase both overall and progression-free survival significantly, whilst having few side effects and maintaining a good quality of life for patients, reflecting it as a beneficial therapy in the palliative setting.

Childhood Brain Tumors: A Review of Strategies to Translate CNS Drug Delivery to Clinical Trials.

Brain and spinal tumors affect 1 in 1000 people by 25 years of age, and have diverse histological, biological, anatomical and dissemination characteristics. A mortality of 30-40% means the majority are cured, although two-thirds have life-long disability, linked to accumulated brain injury that is acquired prior to diagnosis, and after surgery or chemo-radiotherapy. Only four drugs have been licensed globally for brain tumors in 40 years and only one for children. Most new cancer drugs in clinical trials do not cross the blood-brain barrier (BBB). Techniques to enhance brain tumor drug delivery are explored in this review, and cover those that augment penetration of the BBB, and those that bypass the BBB. Developing appropriate delivery techniques could improve patient outcomes by ensuring efficacious drug exposure to tumors (including those that are drug-resistant), reducing systemic toxicities and targeting leptomeningeal metastases. Together, this drug delivery strategy seeks to enhance the efficacy of new drugs and enable re-evaluation of existing drugs that might have previously failed because of inadequate delivery. A literature review of repurposed drugs is reported, and a range of preclinical brain tumor models available for translational development are explored.

Transition From Diencephalic Syndrome to Hypothalamic Obesity in Children With Suprasellar Low Grade Glioma: A Case Series.

Background: Children with suprasellar low grade glioma (LGG) frequently develop problems to maintain their body weight within the normal range, due to hypothalamic dysfunction. Hypothalamic damage may result in the diencephalic syndrome (DS), characterized by underweight or failure to thrive, but also in hypothalamic obesity (HO). Children with LGG presenting with DS at young age often develop HO later in life. The underlying pathophysiology for this change in body mass index (BMI) is not understood. Previous hypotheses have focused on the tumor or its treatment as the underlying cause. To better understand its etiology, we aimed to relate changes in BMI over time in children with suprasellar LGG presenting with DS to age, tumor progression, treatment, and endocrine function. We hypothesize that the development of HO in children with LGG presenting with DS is related to maturation status of the hypothalamus at time of injury and thus age. Methods: In this retrospective case series, all cases diagnosed in the Netherlands with suprasellar located LGG, currently treated or followed, with a history of DS developing into HO were included. Results: In total, 10 children were included. Median age at LGG diagnosis was 1.5 years (range 0.4-5.5), median BMI SDS was -2.64. The children developed overweight at a median age of 4.5 years (2.2-9.8). The median total difference in BMI SDS between underweight and obesity was +5.75 SDS (4.5-8.7). No association could be found between transition of DS to HO and onset of a pituitary disorder (present in 70.0%), surgery, chemotherapy, or tumor behavior. Two had developed central precocious puberty (CPP), both while having underweight or normal weight. Conclusion: The shift from DS to HO in children with hypothalamic LGG may be associated with age and not to tumor behavior, treatment characteristics or pituitary function. The development of CPP in these children seems not to be related to obesity. Our findings may indicate that the clinical picture of hypothalamic dysfunction reflects the maturation state of the hypothalamus at time of lesioning. Future prospective studies are needed to better understand underlying causative mechanisms of the morbid changes in body weight.

Clinical value of a screening tool for tumor predisposition syndromes in childhood cancer patients (TuPS): a prospective, observational, multi-center study.

Recognizing a tumor predisposition syndrome (TPS) in a child with cancer is of clinical relevance. Earlier we developed a screening tool to increase diagnostic accuracy and clinical efficiency of identifying TPSs in children with cancer. Here we report on the value of this tool in clinical practice. TuPS is a prospective, observational, multi-center study including children newly diagnosed with cancer from 2016 to 2019 in the Netherlands. Children in whom a TPS had been diagnosed before the cancer diagnosis were excluded. The screening tool consists of a checklist, 2D and 3D photographic series and digital assessment of these by a clinical geneticist. If a TPS was suspected, the patient was assessed positive and referred for routine genetic consultation. Primary aim was to assess the clinical value of this new screening tool. Of the 363 included patients, 57% (208/363) were assessed positive. In 15% of patients (32/208), the 2D photographic series with (n = 12) or without (n = 20) 3D photographs were decisive in the positive assessment. In 2% (4/208) of positive assessed patients, a TPS was diagnosed, and in an additional 2% (4/208) a germline variant of uncertain significance was found. Thirty-five negatively assessed patients were evaluated through routine genetic consultation as controls, in none a TPS was detected. Using the screening tool, 57% of the patients were assessed as suspected for having a TPS. No false negative results were identified in the negative control group in the clinical care setting. The observed prevalence of TPS was lower than expected, due to selection bias in the cohort.

Leptomeningeal malignancy of childhood: sharing learning between childhood leukaemia and brain tumour trials.

Leptomeningeal malignancy complicates childhood cancers, including leukaemias, brain tumours, and solid tumours. In leukaemia, such malignancy is thought to invade leptomeninges via the vascular route. In brain tumours, dissemination from the primary tumour, before or after surgery, via CSF pathways is assumed; however, evidence exists to support the vascular route of dissemination. Success in treating leptomeningeal malignancy represents a rate-limiting step to cure, which has been successfully overcome in leukaemia with intensified systemic therapy combined with intra-CSF therapy, which replaced cranial radiotherapy for many patients. This de-escalated CNS-directed therapy is still associated with some neurotoxicity. The balanced benefit justifies exploration of ways to further de-escalate CNS-directed therapy. For primary brain tumours, standard therapy is craniospinal radiotherapy, but attendant risk of acute and delayed brain injury and endocrine deficiencies compounds post-radiation impairment of spinal growth. Alternative ways of treating leptomeninges by intensifying drug therapy delivered to CSF are being investigated-preliminary evidence suggests improved outcomes. This Review seeks to describe methods of intra-CSF drug delivery and drugs in use, and consider how the technique could be modified and additional drugs might be selected for this route of administration.

The coding and non-coding transcriptional landscape of subependymal giant cell astrocytomas.

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited neurocutaneous disorder caused by inactivating mutations in TSC1 or TSC2, key regulators of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. In the CNS, TSC is characterized by cortical tubers, subependymal nodules and subependymal giant cell astrocytomas (SEGAs). SEGAs may lead to impaired circulation of CSF resulting in hydrocephalus and raised intracranial pressure in patients with TSC. Currently, surgical resection and mTORC1 inhibitors are the recommended treatment options for patients with SEGA. In the present study, high-throughput RNA-sequencing (SEGAs n = 19, periventricular control n = 8) was used in combination with computational approaches to unravel the complexity of SEGA development. We identified 9400 mRNAs and 94 microRNAs differentially expressed in SEGAs compared to control tissue. The SEGA transcriptome profile was enriched for the mitogen-activated protein kinase (MAPK) pathway, a major regulator of cell proliferation and survival. Analysis at the protein level confirmed that extracellular signal-regulated kinase (ERK) is activated in SEGAs. Subsequently, the inhibition of ERK independently of mTORC1 blockade decreased efficiently the proliferation of primary patient-derived SEGA cultures. Furthermore, we found that LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 were overexpressed at both gene and protein levels in SEGA compared to control tissue. Taken together LAMTOR1-5 can form a complex, known as the 'Ragulator' complex, which is known to activate both mTORC1 and MAPK/ERK pathways. Overall, this study shows that the MAPK/ERK pathway could be used as a target for treatment independent of, or in combination with mTORC1 inhibitors for TSC patients. Moreover, our study provides initial evidence of a possible link between the constitutive activated mTORC1 pathway and a secondary driver pathway of tumour growth.

Prenatal exposure to organohalogen compounds and children's mental and motor development at 18 and 30 months of age.

BACKGROUND: Organohalogen compounds (OHCs), i.e. polychlorinated biphenyls (PCBs, are wide-spread environmental pollutants known to be neurotoxic for the developing brain. The hydroxylated metabolites of PCBs, OH-PCBs, might be even more toxic due to their structure and interference with thyroid hormone metabolism. We found that prenatal exposure to OH-PCBs was associated with thyroid hormone metabolism at toddler age. Little, however, is known about the neurotoxicity of OH-PCBs in humans. OBJECTIVES: To determine whether prenatal background exposure to OHCs has an effect on mental and motor development in children at the age of 18 and 30 months. METHODS: One hundred and eighty-one healthy mother-infant pairs were included in this observational study performed in the Netherlands. We measured maternal pregnancy levels of PCB-153 and three OH-PCBs. In one part of the cohort we measured another nine PCBs and three OH-PCBs and in the other part we measured five brominated diphenyl ethers (BDEs), dichloro-diphenyldichloroethylene (p,p'-DDE), pentachlorophenol (PCP), and hexabromocyclododecane (HBCDD). We used the mental development index (MDI) and the motor development index (PDI) of the Bayley Scales of Infant Development II (BSID-II) to assess children's mental and motor development (mean = 100; delayed score <85). RESULTS: Higher prenatal PCB-153 levels were associated with a delayed MDI score at 18 months. None of the other compounds were associated with a delayed score, but several associations were found between OHC levels and BSID-II scores. The sum of all six OH-PCBs and three individual OH-PCBs, 4-OH-PCB-107, 3-OH-PCB-153, and 4'-OH-PCB-172, correlated positively with MDI at 30 months. The compound 3'-OH-PCB-138 showed a similar trend. A higher 4-OH-PCB-187 was associated with a lower MDI at 18 months. We found a similar trend for higher BDE-99. Higher BDE levels were associated with higher PDI at 18 months. The levels of p,p'-DDE-, PCP, and HBCDD were not associated with BSID-II scores at 18 months. CONCLUSIONS: Higher prenatal levels of PCB-153 were associated with a delayed MDI score at 18 months. None of the other compounds were associated with a delayed score, but several associations were found between OHC levels and BSID-II scores. Prenatal OH-PCBs were positively associated with mental development at 30 months, whereas one OH-PCB was negatively associated at 18 months. BDE levels were positively associated with psychomotor development. Prenatal p,p'-DDE, PCP, and HBCDD levels were not associated with neurodevelopment at 18 months.

Chemical modulation of autophagy as an adjunct to chemotherapy in childhood and adolescent brain tumors.

Brain tumors are the leading cause of cancer-related death in children and are the most challenging childhood cancer in relation to diagnosis, treatment, and outcome. One potential novel strategy to improve outcomes in cancer involves the manipulation of autophagy, a fundamental process in all cells. In cancer, autophagy can be thought of as having a "Janus"-like duality. On one face, especially in the early phases of cancer formation, autophagy can act as a cellular housekeeper to eliminate damaged organelles and recycle macromolecules, thus acting as tumor suppressor. On the other face, at later stages of tumor progression, autophagy can function as a pro-survival pathway in response to metabolic stresses such as nutrient depravation, hypoxia and indeed to chemotherapy itself, and can support cell growth by supplying much needed energy. In the context of chemotherapy, autophagy may, in some cases, mediate resistance to treatment. We present an overview of the relevance of autophagy in central nervous system tumors including how its chemical modulation can serve as a useful adjunct to chemotherapy, and use this knowledge to consider how targeting of autophagy may be relevant in pediatric brain tumors.

Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma.

The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog), group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma.

Intracystic interferon-alpha in pediatric craniopharyngioma patients: an international multicenter assessment on behalf of SIOPE and ISPN.

BACKGROUND: Craniopharyngiomas are frequent hypothalamo-pituitary tumors in children, presenting predominantly as cystic lesions. Morbidity from conventional treatment has focused attention on intracystic drug delivery, hypothesized to cause fewer clinical consequences. However, the efficacy of intracystic therapy remains unclear. We report the retrospective experiences of several global centers using intracystic interferon-alpha. METHODS: European Société Internationale d'Oncologie Pédiatrique and International Society for Pediatric Neurosurgery centers were contacted to submit a datasheet capturing pediatric patients with cystic craniopharyngiomas who had received intracystic interferon-alpha. Patient demographics, administration schedules, adverse events, and outcomes were obtained. Progression was clinical or radiological (cyst reaccumulation, novel cysts, or solid growth). RESULTS: Fifty-six children (median age, 6.3 y) from 21 international centers were identified. Median follow-up from diagnosis was 5.1 years (0.3-17.7 y). Lesions were cystic (n = 22; 39%) or cystic/solid (n = 34; 61%). Previous progression was treated in 43 (77%) patients before interferon use. In such cases, further progression was delayed by intracystic interferon compared with the preceding therapy for cystic lesions (P = 0.0005). Few significant attributable side effects were reported. Progression post interferon occurred in 42 patients (median 14 mo; 0-8 y), while the estimated median time to definitive therapy post interferon was 5.8 (1.8-9.7) years. CONCLUSIONS: Intracystic interferon-alpha can delay disease progression and potentially offer a protracted time to definitive surgery or radiotherapy in pediatric cystic craniopharyngioma, yet demonstrates a favorable toxicity profile compared with other therapeutic modalities-important factors for this developing age group. A prospective, randomized international clinical trial assessment is warranted.

Neurofibromatosis type 1 associated low grade gliomas: A comparison with sporadic low grade gliomas.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which codes for neurofibromin, a large protein involved in the MAPK- and the mTOR-pathway through RAS-RAF signalling. NF1 is a known tumour predisposition syndrome, associated with different tumours of the nervous system including low grade gliomas (LGGs) in the paediatric population. The focus of this review is on grade I pilocytic astrocytomas (PAs), the most commonly observed histologic subtype of low grade gliomas in NF1. Clinically, these PAs have a better prognosis and show different localisation patterns than their sporadic counterparts, which are most commonly associated with a KIAA1549:BRAF fusion. In this review, possible mechanisms of tumourigenesis in LGGs with and without NF1 will be discussed, including the contribution of different signalling pathways and tumour microenvironment. Furthermore we will discuss how increased understanding of tumourigenesis may lead to new potential targets for treatment.

Highlights of Children with Cancer UK's Workshop on Drug Delivery in Paediatric Brain Tumours.

The first Workshop on Drug Delivery in Paediatric Brain Tumours was hosted in London by the charity Children with Cancer UK. The goals of the workshop were to break down the barriers to treating central nervous system (CNS) tumours in children, leading to new collaborations and further innovations in this under-represented and emotive field. These barriers include the physical delivery challenges presented by the blood-brain barrier, the underpinning reasons for the intractability of CNS cancers, and the practical difficulties of delivering cancer treatment to the brains of children. Novel techniques for overcoming these problems were discussed, new models brought forth, and experiences compared.

Developmental trajectories from birth to school age in healthy term-born children.

OBJECTIVE: To determine the stability of the scores obtained on tests of motor development from birth until school age in healthy, term singletons and to determine if early motor scores are associated with more complex cognitive functions at school age, such as attention and memory. PATIENTS AND METHODS: This longitudinal, prospective cohort study included 77 infants. The motor development of these infants was assessed during the neonatal period with Prechtl's neurologic examination; in early infancy with Touwen's neurologic examination and general movement assessment; at toddler age with Hempel's neurologic examination and the Psychomotor Developmental Index from the Bayley Scales of Infant Development; and at school age with the Movement Assessment Battery for Children. Cognition was determined at toddler age with the Mental Developmental Index from the Bayley Scales of Infant Development; and at school age with an intelligence test and attention and memory tests. RESULTS: The mean absolute difference in standardized motor scores for all time points was 1.01 SD (95% confidence interval: 0.91-1.11). Only the explained proportions of variance of maternal socioeconomic status and verbal intelligence were significant for sustained attention and verbal memory (r(2) = 0.104, P = .030 and r(2) = 0.074, P = .027), respectively. The children's scores on early motor tests added little value for their motor and cognitive development at school age. CONCLUSIONS: In healthy children the stability of motor development from birth until school age is low. Maternal socioeconomic status and verbal intelligence rather than the infants' scores on early motor tests signified added value for complex cognitive functions at school age.

Prenatal exposure to organohalogens, including brominated flame retardants, influences motor, cognitive, and behavioral performance at school age.

BACKGROUND: Organohalogen compounds (OHCs) are known to have neurotoxic effects on the developing brain. OBJECTIVE: We investigated the influence of prenatal exposure to OHCs, including brominated flame retardants, on motor, cognitive, and behavioral outcome in healthy children of school age. METHODS: This study was part of the prospective Groningen infant COMPARE (Comparison of Exposure-Effect Pathways to Improve the Assessment of Human Health Risks of Complex Environmental Mixtures of Organohalogens) study. It included 62 children in whose mothers the following compounds had been determined in the 35th week of pregnancy: 2,2'-bis-(4 chlorophenyl)-1,1'-dichloroethene, pentachlorophenol (PCP), polychlorinated biphenyl congener 153 (PCB-153), 4-hydroxy-2,3,3',4',5-pentachlorobiphenyl (4OH-CB-107), 4OH-CB-146, 4OH-CB-187, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), BDE-99, BDE-100, BDE-153, BDE-154, and hexabromocyclododecane. Thyroid hormones were determined in umbilical cord blood. When the children were 5-6 years of age, we assessed their neuropsychological functioning: motor performance (coordination, fine motor skills), cognition (intelligence, visual perception, visuomotor integration, inhibitory control, verbal memory, and attention), and behavior. RESULTS: Brominated flame retardants correlated with worse fine manipulative abilities, worse attention, better coordination, better visual perception, and better behavior. Chlorinated OHCs correlated with less choreiform dyskinesia. Hydroxylated polychlorinated biphenyls correlated with worse fine manipulative abilities, better attention, and better visual perception. The wood protective agent (PCP) correlated with worse coordination, less sensory integrity, worse attention, and worse visuomotor integration. CONCLUSIONS: Our results demonstrate for the first time that transplacental transfer of polybrominated flame retardants is associated with the development of children at school age. Because of the widespread use of these compounds, especially in the United States, where concentrations in the environment are four times higher than in Europe, these results cause serious concern.

Serum concentrations of neutral and phenolic organohalogens in pregnant women and some of their infants in The Netherlands.

As part of a large European Union (EU)-funded comparative toxicology and human epidemiology study, EU-Compare, a selection of organohalogen compounds (OHCs) was analyzed in maternal serum, collected at the 35th week of pregnancy, and in cord serum of a number of their infants to determine maternal concentrations and to investigate the extent of transplacental transfer of these compounds. Eight neutral OHCs were analyzed: one polychlorinated biphenyl (PCB: CB-153),4,4'-DDE, five polybrominated diphenyl ethers (PBDEs: BDE-47, BDE-99, BDE-100, BDE-153, and BDE-154), and hexabromocyclododecane (HBCDD). Five phenolic OHCs were analyzed: three hydroxylated PCBs (40H-CB-107, 40H-CB-146, and 40H-CB-187), one hydroxylated PBDE (60H-BDE-47), and pentachlorophenol (PCP). All OHCs, except 60H-BDE-47, were present in maternal and cord serum. The historically identified OHCs showed the highest concentration: 4,4'-DDE (median value 89 ng/g lipid in maternal serum and 68 ng/g lipid in cord serum) and PCP (median value 970 pg/g serum in maternal serum and 1500 pg/g serum in cord serum). HBCDD and the PBDEs were present at much lower concentrations. We conclude that OHCs are present in the serum of pregnant women, and all compounds tested are transferred over the placenta. Because transfer is occurring at a critical stage of infant development, investigation of the health impact is urgent.

Nonabsorbable dietary fat enhances disposal of 2,2',4,4'-tetrabromodiphenyl ether in rats through interruption of enterohepatic circulation.

Polybrominated diphenyl ethers are lipophilic persistent organic pollutants (POPs), which accumulate in the environment, leading to human exposure. The compounds exert a negative impact on human health. Strategies to prevent or diminish their accumulation in humans are required. We investigated in rats whether the disposal rate of 14C-labeled tetrabromodiphenyl ether (BDE-47) could be enhanced by increasing fecal fat excretion through dietary treatment with nonabsorbable fat (sucrose polyester, SPE). As compared to control rats, SPE treatment increased fecal excretion rates of fat (+188%, p < 0.05) and 14C-BDE-47 (+291%, p < 0.05). On the basis of biliary secretion and fecal excretion rates of 14C-BDE-47, SPE effectively inhibited the enterohepatic circulation of 14C-BDE-47. In conclusion, dietary supplementation of nonabsorbable fat can enhance excretion of hydrophobic POPs by interruption of their enterohepatic circulation. Our data indicate that this strategy could decrease concentrations of hydrophobic POPs in the human body and thereby their impact on human health.