Application of computational systems biology to explore environmental toxicity hazards.

Background: Computer-based modeling is part of a new approach to predictive toxicology. Objectives: We investigated the usefulness of an integrated computational systems biology approach in a case study involving the isomers and metabolites of the pesticide dichlorodiphenyltrichloroethane (DDT) to ascertain their possible links to relevant adverse effects. Methods: We extracted chemical–protein association networks for each DDT isomer and its metabolites using ChemProt, a disease chemical biology database that includes both binding and gene expression data, and we explored protein–protein interactions using a human interactome network. To identify associated dysfunctions and diseases, we integrated protein–disease annotations into the protein complexes using the Online Mendelian Inheritance in Man database and the Comparative Toxicogenomics Database. Results: We found 175 human proteins linked to p,p'-DDT, and 187 to o,p'-DDT. Dichlorodiphenyldichloroethylene (p,p'-DDE) was the metabolite with the highest number of links, with 52. We grouped proteins for each compound based on their disease annotations. Although the two data sources differed in linkage to diseases, integrated results predicted that most diseases were linked to the two DDT isomers. Asthma was uniquely linked with p,p'-DDT, and autism with o,p'-DDT. Several reproductive and neurobehavioral outcomes and cancer types were linked to all three compounds. Conclusions: Computer-based modeling relies on available information. Although differences in linkages to proteins may be due to incomplete data, our results appear meaningful and suggest that the parent DDT compounds may be responsible for more disease connections than the metabolites. The findings illustrate the potential use of computational approaches to toxicology

Neurodevelopment and Endocrine Disruption

In this article I explore the possibility that contaminants contribute to the increasing prevalence of attention deficit hyperactivity disorder, autism, and associated neurodevelopmental and behavioral problems in developed countries. I discuss the exquisite sensitivity of the embryo and fetus to thyroid disturbance and provide evidence of human in utero exposure to contaminants that can interfere with the thyroid. Because it may never be possible to link prenatal exposure to a specific chemical with neurodevelopmental damage in humans, I also present alternate models where associations have been made between exposure to specific chemicals or chemical classes and developmental difficulties in laboratory animals, wildlife, and humans

Exposure to Hexachlorobenzene during Pregnancy and Children’s Social Behavior at 4 Years of Age

BACKGROUND: Hexachlorobenzene (HCB) is an organochlorine chemical that has been used in agriculture and industrial processes. Behavioral impairment after HCB exposure has been described in animal models, but little information is available in humans. OBJECTIVES: Our goal was to study the association of prenatal exposure to HCB with the social behavior of preschool children. METHODS: Two birth cohorts in Ribera d’Ebre and Menorca (Spain) were set up between 1997 and 1999 (n = 475). The California Preschool Social Competence Scale and the Attention-Deficit Hyperactivity Disorder (ADHD) were scored by each 4-year-old child’s teacher. Organochlorine compounds were measured in cord serum. Children’s diet and parental sociodemographic information were obtained through questionnaire. RESULTS: Children with concentrations of HCB > 1.5 ng/mL at birth had a statistically significant increased risk of having poor Social Competence [relative risk (RR) = 4.04; 95% confidence interval (CI), 1.76–9.58] and ADHD (RR = 2.71; 95% CI, 1.05–6.96) scores. No association was found between HCB and the cognitive and psychomotor performance of these children. CONCLUSIONS: Prenatal exposure to current concentrations of HCB in Spain is associated with a decrease in the behavioral competence at preschool ages. These results should be considered when evaluating the potential neurotoxicologic effects of HCB

Maternal Fish Consumption, Hair Mercury, and Infant Cognition in a U.S. Cohort

Fish and other seafood may contain organic mercury but also beneficial nutrients such as n-3 polyunsaturated fatty acids. We endeavored to study whether maternal fish consumption during pregnancy harms or benefits fetal brain development. We examined associations of maternal fish intake during pregnancy and maternal hair mercury at delivery with infant cognition among 135 mother–infant pairs in Project Viva, a prospective U.S. pregnancy and child cohort study. We assessed infant cognition by the percent novelty preference on visual recognition memory (VRM) testing at 6 months of age. Mothers consumed an average of 1.2 fish servings per week during the second trimester. Mean maternal hair mercury was 0.55 ppm, with 10% of samples > 1.2 ppm. Mean VRM score was 59.8 (range, 10.9–92.5). After adjusting for participant characteristics using linear regression, higher fish intake was associated with higher infant cognition. This association strengthened after adjustment for hair mercury level: For each additional weekly fish serving, offspring VRM score was 4.0 points higher [95% confidence interval (CI), 1.3 to 6.7]. However, an increase of 1 ppm in mercury was associated with a decrement in VRM score of 7.5 (95% CI, –13.7 to –1.2) points. VRM scores were highest among infants of women who consumed > 2 weekly fish servings but had mercury levels ≤1.2 ppm. Higher fish consumption in pregnancy was associated with better infant cognition, but higher mercury levels were associated with lower cognition. Women should continue to eat fish during pregnancy but choose varieties with lower mercury contamination

Prenatal Organochlorine Exposure and Measures of Behavior in Infancy Using the Neonatal Behavioral Assessment Scale (NBAS)

Background: Previous literature suggests an association between organochlorines and behavioral measures in childhood, including inattention. Objective: This study was designed to assess whether prenatal organochlorine exposure is associated with measures of attention in early infancy. Methods: We investigated an association between cord serum polychlorinated biphenyls (PCBs) and p,p′-dichlorodiphenyl dichloroethene (DDE) levels and measures of attention from the Neonatal Behavioral Assessment Scale (NBAS) in a cohort of 788 infants born 1993–1998 to mothers residing near a PCB-contaminated harbor and Superfund site in New Bedford, Massachusetts. Results: Medians (ranges) for the sum of four prevalent PCB congeners and DDE levels were 0.19 (0.01–4.41) and 0.30 (0–10.29) ng/g serum, respectively. For the 542 subjects with an NBAS exam at 2 weeks, we observed consistent inverse associations between cord serum PCB and DDE levels and NBAS measures of alertness, quality of alert responsiveness, cost of attention, and other potential attention-associated measures including self-quieting and motor maturity. For example, the decrement in quality of alert responsiveness score was −0.51 (95% confidence interval, −0.99 to −0.03) for the highest quartile of exposure to the sum of four prevalent PCB congeners compared with the lowest quartile. We found little evidence for an association with infant orientation, habituation, and regulation of state, assessed as summary cluster measures. Conclusions: Our findings provide evidence for an association between low-level prenatal PCB and DDE exposures and poor attention in early infancy. Further analyses will focus on whether organochlorine-associated decrements in attention and attention-related skills in infancy persist in later childhood

The Landscape Archaeology of Knettishall Heath, Suffolk and its Implications

This paper briefly describes the results of archaeological fieldwork carried out in an area of heathland, currently managed as a nature reserve, in East Anglia. Although the earthworks recorded are for the most part unremarkable, they demonstrate the variety and intensity of human exploitation which shaped this ‘traditionally managed’ habitat. They also serve to emphasise the extent to which modern conservation management can radically change the long-term character of individual places

Knowlton Circles: A Later Neolithic and Early Bronze Age Ceremonial Complex and Its Environs—A Review

The larger henge monuments of Wessex have been the focus of detailed archaeological investigation for over a century and consequently their study has provided a greater, albeit fragmentary, understanding of later Neolithic society. For the most part such studies have continued to show that these great mega-structures of the third millennium B.C. persist as beacons of ceremonial functionality into which later societies invested much of themselves, intellectually, spiritually and unquestionably physically. While Stonehenge, Avebury and Durrington Walls continue to attract a great deal of attention with ongoing research, comparable sites in Dorset have been less well researched. Two campaigns of archaeological investigation undertaken in the Allen Valley of east Dorset by the author have focussed upon the complex of earthworks at Knowlton and additionally at one of three broadly contemporary barrow cemeteries located nearby. The findings from these investigations are beginning to shed more light on the possible origins and development of these important but weakly understood landscapes. This paper outlines some of the main findings from these investigations and posits a chronological framework for the integration of a group of monuments that formed both a ceremonial landscape and a geographical and spiritual home for communities that lasted for a thousand years

Lactational Exposure to Polychlorinated Biphenyls, Dichlorodiphenyltrichloroethane, and Dichlorodiphenyldichloroethylene and Infant Neurodevelopment: An Analysis of the Pregnancy, Infection, and Nutrition Babies Study

BackgroundPolychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDT) are persistent, bioaccumulative, and toxic pollutants that were broadly used in the United States until the 1970s. Common exposure to PCBs, DDT, and dichlorodiphenyldichloroethylene (DDE), the most stable metabolite of DDT, may influence children’s neurodevelopment, but study results are not consistent.ObjectivesWe examined the associations between lactational exposure to PCBs, DDT, and DDE and infant development at 12 months, using data from the Pregnancy, Infection, and Nutrition Babies Study, 2004–2006.MethodsWe measured PCBs, DDT, and DDE in breast milk at the third month postpartum. Lactational exposure of these chemicals was estimated by the product of chemical concentrations and the duration of breast-feeding. Infant development at 12 months of age was measured by the Mullen Scales of Early Learning (n = 231) and the Short Form: Level I (infant) of the MacArthur–Bates Communicative Development Indices (n = 218).ResultsNo consistent associations were observed between lactational exposure to PCBs, DDT, and DDE through the first 12 months and the measures of infant development. However, DDE was associated with scoring below average on the gross motor scale of the Mullen among males only (adjusted odds ratio = 1.9; 95% confidence interval, 1.1–3.3).ConclusionInfant neurodevelopment at 12 months of age was not impaired by PCBs, DDT, and DDE at the concentrations measured here, in combination with benefits from long duration of breast-feeding in this population

Local and exotic sources of sarsen debitage at Stonehenge revealed by geochemical provenancing

The application of novel geochemical provenancing techniques has changed our understanding of the construction of Stonehenge, by identifying West Woods on the Marlborough Downs as the likely source area for the majority of the extant sarsen megaliths at the monument. In this study, we apply the same techniques to saccharoid sarsen fragments from three excavations within and outwith the main Sarsen Circle to expand our understanding of the provenance of sarsen debitage present at the monument. Through pXRF analysis, we demonstrate that the surface geochemistry of 1,028 excavated sarsen fragments is significantly affected by subsurface weathering following burial in a way that cannot be overcome by simple cleaning. However, we show that this effect is surficial and does not have a volumetrically significant impact, thus permitting the subsequent use of whole-rock analytical methods. Comparison of ICP-AES and ICP-MS trace element data from 54 representative sarsen fragments with equivalent data from Stone 58 at Stonehenge demonstrates that none are debitage produced during the dressing of this megalith or its 49 chemical equivalents at the monument. Further inspection of the ICP-MS data reveals that 22 of these fragments fall into three distinct geochemical ‘families’. None of these families overlap with the geochemical signature of Stone 58 and its chemical equivalents, implying that sarsen imported from at least a further three locations (in addition to West Woods) is present at Stonehenge. Comparison of immobile trace element signatures from the 54 excavated sarsen fragments against equivalent data for 20 sarsen outcrop areas across southern Britain shows that 15 of the fragments can be linked to specific localities. Eleven of these were likely sourced from Monkton Down, Totterdown Wood and West Woods on the Marlborough Downs (25–33 km north of Stonehenge). Three fragments likely came from Bramdean, Hampshire (51 km southeast of Stonehenge), and one from Stoney Wish, East Sussex (123 km to the southeast). Technological analysis and refitting shows that one of the fragments sourced from Monkton Down was part of a 25.7 cm × 17.9 cm flake removed from the outer surface of a large sarsen boulder, most probably during on-site dressing. This adds a second likely source area for the sarsen megaliths at Stonehenge in addition to West Woods. At this stage, we can only speculate on why sarsen from such diverse sources is present at Stonehenge. We do not know whether the fragments analysed by ICP-MS were removed from (i) the outer surface of Stones 26 or 160 (which are chemically distinct to the other extant sarsen megaliths), (ii) one of the c.28 sarsen megaliths and lintels from the c.60 erected during Stage 2 of the construction of Stonehenge that may now be missing from the monument, or (iii) one of the dismantled and destroyed sarsen megaliths associated with Stage 1 of the monument. With the exception of the fragment sourced from Monkton Down, it is also possible that the analysed fragments were (iv) pieces of saccharoid sarsen hammerstones or their pre-forms, or (v) small blocks brought on-site for ceremonial or non-ceremonial purposes