bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of protein level and flushing method on the reproductive performance of rabbits
Authors: IYEGHE‐ERAKPOTOBOR Grace T. , OLORUNJU Shade A. S. , OYEDIPE Emmanuel O.
Published: September 2010

Fifty‐five New Zealand white × California cross‐bred female rabbits were used to study the effect of protein level and flushing method on the reproductive performance of rabbits. The treatments consisted of three protein diets (18, 20 and 24% crude protein (CP)) and three flushing methods in a 3 × 3 factorial design. The flushing methods consisted of (i) flushing multiparous does and feeding a 16% CP diet during pregnancy; (ii) flushing multiparous does and feeding an 18% CP diet during pregnancy; and (iii) flushing nulliparous does and feeding an 18% CP diet during pregnancy. Flushing rabbits with different levels of protein did not significantly affect gestation length, litter size and mortality of kits. The trend showed an increase in litter weight with the increase in protein level from 18 to 24%. However, kits from does flushed with 24% CP had a higher individual kit weight gain than those on 20 and 18% CP. Gestation length, total litter size at birth, number of kits dead at birth and number of kits dead at 21 days post‐partum were not affected by flushing methods. There was, however, a significant effect of the flushing method on the number of kits alive at birth, and 7, 14 and 21 days post‐partum. Nulliparous does flushed and maintained on 18% CP during pregnancy had a significantly higher number of kits alive at birth, and 7, 14 and 21 days post‐partum. Litter weight was significantly higher for nulliparous does at 7, 14 and 21 days compared with that of multiparous does flushed and placed on a 16 or 18% CP diet during pregnancy. Protein intake during pregnancy had a significant effect on litter birthweight. Nulliparous and multiparous does flushed and placed on an 18% CP diet during pregnancy had a significantly higher litter birthweight than multiparous does flushed and placed on a 16% CP diet during pregnancy. The effect of protein level during pregnancy on the number of kits alive at birth was not significant. There was no interaction between protein level and flushing method on the reproductive performance of rabbits.
Comparison of fattening performance in Brahman grade cattle (Bos indicus) and crossbred water buffalo (Bubalus bubalis) fed on high roughage diet
Authors: LAPITAN Rosalina M. , DEL BARRIO Arnel N. , KATSUBE Osamu , BAN‐TOKUDA Tomomi , ORDEN Edgar A. , ROBLES Alberto Y. , CRUZ Libertado C. , KANAI Yukio , FUJIHARA Tsutomu
Published: September 2010

The objective of this study was to compare the fattening performance in Brahman grade cattle (crossbred cattle) and crossbred water buffalo at the same young age and fed with high roughage based fattening rations in the Philippines. Ten crossbred cattle and 10 crossbred water buffalo, aged between 18 and 24 months old were used in this experiment. The animals were fed diets consisting of 85% Napier or Para grass and 15% concentrate mixture (CM) on a dry matter (DM) basis. The grass, total DM intake and bodyweight gain were significantly (P < 0.01) higher for the crossbred water buffalo than for the cattle. There was no species significant difference in the digestion coefficient and feed conversion rate between the crossbred cattle and water buffalo. The return over feed cost for fattening was significantly (P < 0.05) higher in the crossbred water buffalo than in the cattle. These results clearly indicate that under high roughage‐based fattening rations, young crossbred water buffalo are better able to utilize the roughage and they perform better in terms of feed intake and live weight gains than the crossbred cattle in the Philippines.
Comparison of the bioactive components of the ecotypes and cultivars of plantain (Plantago lanceolata L.) herbs
Authors: AL‐MAMUN Mohammad , ABE Daisuke , KOFUJITA Hisayoshi , TAMURA Yoshifumi , SANO Hiroaki
Published: September 2010

The concentrations of the bioactive components, acteoside, aucubin and catalpol, and the production yield, crude protein (CP) and crude ash contents in 25 ecotypes (Et) of plantain (PL, Plantago lanceolata L.), found in northern Japan, and commercial cultivars, Grasslands Lancelot (GL) and Ceres Tonic (CT), were investigated. The quantitative determination of bioactive components was performed by high performance liquid chromatography. The acteoside content of some of the 25 Et was significantly higher (P < 0.05) than CT and numerically higher than GL and other Et. Most of the Et had numerically higher concentrations of catalpol and aucubin than the GL and CT. The CP and crude ash content of the Et were comparable with those of the GL and CT. The dry matter (DM) yields of some of the Et was numerically greater than that of the cultivars. The present data suggest that most of the Et are comparable to the cultivars in respect to the concentration of bioactive components and DM yield as well as CP and crude ash contents and could be used as pasture like GL and CT.
The Trollopian Geopolitical Aesthetic
Authors: Goodlad Lauren M. E.
Published: September 2010

Trollope’s reputation as a formally dull post‐1848 realist persists even though the period of his Palliser series (1864–1879) was characterized by intense political and imperial dynamism. While most of Trollope’s novels during this period exemplify a historically engaged realism,The Eustace Diamondsis distinct for its rare meditation on empire in South Asia—a topic that Trollope seems purposely to have avoided. Trollope’s fourth Palliser novel captures the vexed ethics of a so‐called liberal imperialism through two classic characters—Lucy Morris and Lord Fawn—and their interactions with the Sawab of Mygawb, a “non‐character”who marks the novel’s geopolitical unconscious. But the novel’s most formally distinct features revolve around representation of Lizzie Eustace, who figures Trollope’s uneasiness over the New Imperial era’s neo‐feudal aesthetics. Trollope associated the New Imperialism with Benjamin Disraeli whose Jewish ethnicity he tied to a “conjuring” political agency that could master the theaters of mass democracy and imperial expansion. InThe Eustace Diamonds, Lizzie becomes the embodiment of an actively performed New Imperial aesthetic. As a Disraeli‐like schemer, she introduces a stylistic referentiality that is alien to Trollope’s ‘pellucid’ linguistic ideal. Where Trollope’s sociological and global capitalist novels offer nuanced aesthetic capture, Lizzie marks the representational limits of such realism. Like the Sawab, she is the sign of a Trollopian power to stretch form beyond the crude anti‐realism of the racialized scapegoat.
Touching Texts: The Haptic Sense in Modernist Literature
Authors: Garrington Abbie
Published: September 2010

The haptic sense combines touch – the reaching and touching of any part of the human skin – with kinaesthesis, or the body’s appreciation of its own movement. It also involves proprioception, a bodily sense of position within space. It has become a major focus of attention in academic studies of recent years, with film theorists, sociologists, computer scientists, physiologists and human geographers all attempting to describe with accuracy the elusive sense of touch. However, no full account has been given of the role of the haptic in literature, either as a subject of fiction or as the basis for a mode of writing. In the case of modernist texts, these seem particularly strange oversights, as the period was one in which human bodies were becoming accustomed to startling new experiences – including most importantly the cinema and mechanised transport – that transformed the human sense of movement and of tactile interactions between body and world. Several culturally attuned modernist theorists noted the haptic transformations of life in the early twentieth century. Walter Benjamin was to claim that modernist existence could only be fully apprehended through ‘tactile appropriation,’ while F.T. Marinetti’s ‘Tactilism’ manifesto lamented the poor thought‐conducting qualities of the skin and suggested tactile engagement as a route not only to great art but to better human understanding (Benjamin 233; Marinetti). Meanwhile, many authors of the modernist avant‐garde were recognising and evoking the importance of touch, kinaesthesis and proprioception within their texts. The work of Virginia Woolf, Dorothy Richardson and D.H. Lawrence, amongst others, demonstrates that the haptic sense was a vital concern of the modernist period – not simply part of the fabric of daily life, but also a pressing matter to be identified and analysed within, and even re‐created by, literature. In fact, the period is poised at the mid‐point of the history of theories of the haptic, which stretches from nineteenth century physiological and art historical studies, to our present day, multi‐disciplinary attention to skin, touch and bodily movement. Tracing this theoretical history, and identifying a flowering of interest in the haptic sense in the modernist period, provides an opportunity to view modernist writing from a new perspective. By defining the haptic, and by looking at its role in the work of some canonical modernist writers, this article aims at exploring the promise of a haptic‐oriented analysis for the study of modernist literature.
Effects of Salvianolic Acid A on Oxidative Stress and Liver Injury Induced by Carbon Tetrachloride in Rats
Authors: Wu Zhi‐ming , Wen Tao , Tan Yu‐fen , Liu Yan , Ren Feng , Wu Hao
Published: September 2010

Abstract:  In the present study, we investigated the hepatoprotective effects of salvianolic acid A, a novel antioxidant, against oxidative stress and acute liver injury induced by carbon tetrachloride (CCl4) in rats, and the mechanisms underlying its protective effects. Administration of CCl4 to rats caused severe hepatic damage, as demonstrated by the significant increase in the levels of serum alanine aminotransferase, aspartate aminotransferase and classic histological changes including hepatocyte necrosis or apoptosis, haemorrhage, fatty degeneration, etc. Co‐treatment with salvianolic acid A (20 mg/kg, intraperitoneally), a water‐soluble extract from a Chinese traditional drug, Radix Salvia miltiorrhiza, significantly decreased CCl4‐induced hepatotoxicity. Salvianolic acid A not only decreased serum alanine aminotransferase, aspartate aminotransferas levels and ameliorated histopathological manifestations in CCl4‐treated rats, but also reduced oxidative stress, as evidenced by decreased reactive oxygen species production and malondialdehyde concentrations in the liver tissues, combined with elevated hepatic superoxide dismutase activity and gluthathione content. In addition, salvianolic acid A treatment remarkably reduced intrahepatic tumour necrosis factor‐α concentrations and caspase‐3 activities as compared with the CCl4‐treated rats. The results suggested that treatment with salvianolic acid A provides a potent protective effect against acute hepatic damage caused by CCl4 in rats, which may mainly be related to its antioxidative effect.
Effect of Caffeine‐Containing versus Decaffeinated Coffee on Serum Clozapine Concentrations in Hospitalised Patients
Authors: Raaska Kari , Raitasuo Virpi , Laitila Jouko , Neuvonen Pertti J.
Published: September 2010

Abstract: Clozapine and caffeine are metabolised mainly by the cytochrome P4501A2 (CYP1A2) enzyme. Studies suggest that caffeine in coffee inhibits clozapine metabolism and increases serum clozapine concentrations. Our objective was to study whether coffee in the amounts usually consumed has an effect on steady‐state serum clozapine concentrations. A randomised placebo‐controlled cross‐over design with two phases was used. Twelve hospitalised clozapine‐using patients volunteered in the study where, after one‐week run‐in period, either caffeine‐containing or decaffeinated instant coffee was available ad libitum for seven days. Serum concentrations of clozapine, N‐desmethylclozapine, clozapine‐N‐oxide, caffeine, paraxanthine and C‐reactive protein were measured after run‐in period and on days 4 and 8 of the following study phases. Two patients were excluded from the statistical analysis because of non‐compliance based on serum caffeine and paraxanthine determinations. In six fully compliant patients caffeine‐containing coffee increased the mean serum trough concentration of clozapine by 26% (non‐significant (NS), 95% CI −3% to +54%, P=0.07), N‐desmethylclozapine by 6% (95% CI 1% to 12%, P=0.03), and clozapine‐N‐oxide by 7% (NS, 95% CI −6% to +20%, P=0.22). The ratio of N‐desmethylclozapine/clozapine decreased by 13% (NS, 95% CI −1% to +27%, P=0.06) and that of clozapine‐N‐oxide/clozapine by 7% (NS, 95% CI −5% to +17%, P=0.19). In the analysis of combined data (including day 4 data of the four patients compliant up to that point) serum trough concentration of clozapine was 20% (95% CI 3% to 37% to P=0.03) higher, and that of N‐desmethylclozapine 7% (95% CI 2% to 13%, P=0.02) higher during the caffeine phase than during the decaffeinated phase. We conclude that the effect of instant coffee drinking on serum clozapine concentrations is of minor clinical relevance in most of the patients, but some individuals may be more sensitive to this interaction due e.g. to genetic factors. The increase in serum clozapine concentration was most likely due to the inhibition of the CYP1A2 enzyme by caffeine.
Mechanism of Acetaminophen‐Induced Apoptosis in Cultured Cells: Roles of Caspase‐3, DNA Fragmentation Factor, and the Ca2+and Mg2+Endonuclease DNAS1L3
Authors: Boulares A. Hamid , Ren Tao
Published: September 2010

Abstract:We have recently shown that acetaminophen induces many of the apoptotic traits in hepatoma cells and lymphocytes (Boulareset al.(2002d). In an effort to further investigate the mechanism by which non‐metabolized acetaminophen induces apoptosis, we have now examined the roles of caspase‐3, the DNA fragmentation factor, and the poly(ADP‐ribose) polymerase‐1‐regulated Ca2+and Mg2+‐dependent endonuclease DNAS1L3 in the induction of such death process. This was achieved with the use of MCF‐7 cells, a caspase‐3‐deficient breast adenocarcinoma cell line, thymocytes isolated from DFF45 (the inhibitory and chaperone subunit of the DNA fragmentation factor subunit, DFF40) deficient mice, and HeLa cells, a DNAS1L3‐deficient cervical carcinoma cell line. MCF‐7 exhibited a marked resistance to acetaminophen treatment. Ectopic expression of human caspase‐3 significantly potentiated the cytotoxic effect of acetaminophen and promoted the release of cytochrome c into the cytosol of treated cells suggesting a direct role for caspase‐3 in acetaminophen‐induced apoptosis. Expression and cleavage of DFF45 were required but not sufficient for acetaminophen‐induced internucleosomal DNA fragmentation. DFF45 gene knockout rendered thymocytes resistant against acetaminophen‐induced generation of both large and internucleosomal DNA fragments. The treatment of HeLa cells with acetaminophen resulted in internuclesomal DNA fragmentation only after transfection of these cells with a plasmid encoding the DNAS1L3 gene suggesting that this endonuclease is required for acetaminophen‐induced internucleosomal DNA fragmentation. DNAS1L3 expression potentiated the cytotoxic effect of acetaminophen in HeLa cells suggesting an active role in the death process induced by this drug. Altogether, these results demonstrate the specific roles of caspase‐3, DNA fragmentation factor, and DNAS1L3 in the process of acetaminophen‐induced apoptosis in cultured cells.
Effect of Endothelin Antagonism on Contractility, Intracellular Calcium Regulation and Calcium Regulatory Protein Expression in Right Ventricular Hypertrophy of the Rat
Authors: Stessel Heike , Brunner Friedrich
Published: September 2010

Abstract: We have documented the effects of long‐term endothelin receptor antagonism on intracellular Ca2+ regulation and Ca2+ regulatory protein expression in rat hearts with right ventricular hypertrophy without signs of heart failure. Rats were given either a single injection of monocrotaline (50 mg/kg, n=9) resulting in pulmonary hypertension‐induced myocardial hypertrophy, or monocrotaline followed by daily administration of the endothelin subtype‐A receptor antagonist 2‐benzo(1,3)dioxol‐5‐yl‐3‐benzyl‐4‐(4‐methoxy‐phenyl‐)‐4‐oxobut‐2‐enoate‐Na (PD 155080, 50 mg/kg) over 9 weeks (n=8). Hearts from saline‐injected rats served as controls (n=9). Monocrotaline‐treated animals developed marked right‐sided hypertrophy without fibrosis as evident from hydroxyproline measurements, systolic contractility was increased, fully compensating for the increased afterload, but diastolic function was impaired as evident from protracted relaxation and slowed diastolic intracellular Ca2+ handling (measured by aequorin bioluminescence). In hypertrophic hearts, quantitative immunoblotting analyses showed increased levels both of sarco(endo)plasmic reticulum Ca2+‐ATPase (SERCA) and phosphorylated phospholamban, along with decreased levels of total phospholamban, which is in line with strengthened right ventricular systolic function. PD 155080 reversed abnormalities in Ca2+ handling, although SERCA and phospholamban protein levels were not altered (P=not significant versus monocrotaline group). Thus, endothelin‐A receptor antagonism attenuates right ventricular remodeling and improves myocardial Ca2+ handling, but has no discernable effect on elevated expression of SERCA and phospholamban observed in hypertrophic hearts. These data indicate that the hypotensive action of PD 155080 is independent of its effects, if any, on SERCA and its regulation.
Valproic Acid is Known to Cause Hypospadias in Man but does not Reduce Anogenital Distance or Causes Hypospadias in Rats
Authors: Källén Bengt
Published: September 2010

Abstract: The use of valproic acid during human pregnancy increases the risk of hypospadias in the offspring. Rats exposed in utero to valproic acid did not develop hypospadias and even had a slightly increased anogenital distance in males 3–4 days after birth. A classical antiandrogenic drug, flutamide, caused hypospadias as well as a reduction of the anogenital distance in males. At the age of 3 months, rats exposed in utero with either valproic acid or flutamide showed a reduced testicular weight and hypoplasia of tubules, which seemed not to be related to the antiandrogenic activity of flutamide as it did not correlate with the presence of hypospadias. The mechanism through which valproic acid causes hypospadias in man and affects testicular development in rat is unknown. Hypospadias caused by valproic acid in man is apparently not due to anti‐androgenic properties of the drug.
Regulation of Gender‐Dependent CYP2A Expression in Pigs: Involvement of Androgens and CAR
Authors: Gillberg Mette , Skaanild Mette T. , Friis Christian
Published: September 2010

Abstract:The expression of drug metabolizing cytochrome P4502A (CYP2A) is highly gender‐dependent in minipigs with the highest activity in females. In other species, orthologs of CYP2A have been shown to be under the regulation of nuclear receptor constitutive androstane receptor, whereas little is known about regulation in pigs. To investigate the effect of sex hormones on porcine cytochrome P450 CYP2A and CYP3A expression was assessed in liver samples taken before and after castration of sexually mature minipig boars. Removal of the primary androgen source resulted in significant increases of CYP2A mRNA, protein and enzyme activity levels. Likewise, expression of CYP3A was increased, although to a lesser extent. To examine the involvement of constitutive androstane receptor in the regulation of CYP2A, primary porcine hepatocytes were exposed to modulators of murine constitutive androstane receptor and human constitutive androstane receptor activity. The CYP2A activity was significantly increased by exposure to phenobarbital, an indirect activator of constitutive androstane receptor, and the human constitutive androstane receptor‐ligand CITCO. In contrast, no effect was seen following exposure to the potent murine constitutive androstane receptor‐ligand TCPOBOP and the hormonal murine constitutive androstane receptor‐ligands androstenol and oestrone. Thus, the results support that 1) porcine CYP2A is reversibly inhibited by androgens on a transcriptional basisin vivo; 2) the induction profile of CYP2Ain vitroshares similarity with that of human constitutive androstane receptor‐regulated CYPs, indicating an involvement of a porcine constitutive androstane receptor in the regulation of CYP2A.
The L‐Type Calcium Channel Blocker Nimodipine Mitigates Cytoskeletal Proteins Phosphorylation in Dichlorvos‐Induced Delayed Neurotoxicity in Rats
Authors: Choudhary Sanjeev , Verma Suresh Kumar , Raheja Geetu , Kaur Pushpinder , Joshi Kusum , Gill Kiran Dip
Published: September 2010

Abstract: The present investigation was carried out to assess the protective efficacy of nimodipine against dichlorvos‐induced organophosphate induced delayed neurotoxicity (OPIDN). Single subcutaneous dose of dichlorvos (200 mg/kg body weight) led to a consistent increase in the activity of both microtubule associated protein kinases viz. Ca2+/Calmodulin‐dependent and cAMP dependent protein kinases, at all post exposure intervals (day 7, 15 and 21) as compared to that of controls. Autoradiography followed by microdensitometric studies demonstrated enhanced phosphorylation of 55 kDa and 280 kDa proteins in dichlorvos‐exposed animals. These two proteins were confirmed to be tubulin and microtubule associated protein‐2 (MAP‐2) by western blotting. The hyperphosphorylation of these two proteins was shown to interfere with the assembly of neuronal microtubules as shown by electron microscopic studies that may eventually lead to possible disruption of neuronal cytoarchtecture resulting in axonal degeneration. Administration of nimodipine along with dichlorvos brought about a significant reduction in the activities of both the kinases as well as the extent of microtubule associated protein phosphorylation. This indicates that nimodipine, a centrally acting calcium channel blocker, may contribute to the amelioration of dichlorvos induced neurotoxicity by attenuation of calcium mediated disruption of cytoskeletal proteins and hence, calcium channel blockers like nimodipine have great future as new therapeutic agents for OPIDN
Multiple Motor Effects of ATP and their Inhibition by P2Purinoceptor Antagonist, Pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic Acid in the Small Intestine of the Guinea‐Pig
Authors: Barthó Lorand , Undi Sarolta , Benk Rita , Wolf Matyas , Lázár Zsofia , Lénárd Laszlo , Maggi Carlo A.
Published: September 2010

Abstract:Adenosine 5′‐triphosphate (ATP) may be an important neurotransmitter in the gastrointestinal tract. The present study examined the motor effects of exogenous ATP on longitudinally‐oriented preparations of the guinea‐pig isolated ileum and the influence of drugs on the ATP‐induced responses. High micromolar concentrations of ATP caused two types of contraction, a phasic, cholinergic response and a tonic, tetrodotoxin‐resistant contraction. The phasic contraction was reduced by hexamethonium (5×10−5M), but left uninfluenced by capsaicin tachyphylaxis or tachyphylaxis to α,β‐methylene ATP. The tonic response was resistant to atropine, hexamethonium, capsaicin, ω‐conotoxin GVIA, or pretreatment with α,β‐methylene ATP. Both types of ATP‐induced contraction were diminished or abolished by the P2purinoceptor antagonist pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS, 3×10−6and 3×10−5M, respectively). In the precontracted, atropine‐treated ileum ATP (10−6–10−4M) caused guanethidine‐resistant relaxation. This response was not influenced by tetrodotoxin, ω‐conotoxin GVIA, or NG‐nitro‐L‐arginine, but was abolished by apamin (10−7M), and inhibited by PPADS (3×10−5M) or reactive blue 2 (10−5M), in a surmountable manner. A high degree of tachyphylaxis was observed with the relaxant effect of ATP (10−5–10−4M). A high concentration (3×10−4M) of PPADS failed to influence ileum contractions to exogenous acetylcholine or histamine. It is concluded that, in addition to its direct contractile action in the guinea‐pig ileum, ATP can activate (partly preganglionic) cholinergic neurones, an effect whose mechanism is largely different from that of α,β‐methylene ATP. ATP also causes relaxation by a direct, probably P2Y‐receptor‐mediated effect on the smooth muscle. All motor effects of ATP are inhibited by the antagonist PPADS.
Non‐Clinical Safety Studies on Biosimilar Recombinant Human Erythropoietin
Authors: Parnham Michael J. , Schindler‐Horvat Janice , Kozlović Marija
Published: September 2010

Abstract: Recombinant human erythropoietin (rhEPO) is widely used for the treatment of patients with anaemia and its loss of patent protection has stimulated the development of cheaper biosimilar products. However, the quality and comparability of rhEPO products recently marketed in several developing countries is questionable. Paying attention to quality in its isolation, purification and analytical characterization, it has been possible to produce a biosimilar rhEPO that is comparable with the originator product. Non‐clinical safety testing was initially carried out in the absence of a regulatory framework and contributed to the receipt of marketing approval for biosimilar rhEPO in Eastern Europe. Subsequently, this non‐clinical testing was extended to take into account the recent guidelines for similar biological medicinal products published by the European regulatory authorities, which were markedly influenced by the intervening occurrence of pure red cell aplasia in patients taking what proved to be an impure rhEPO product. This Mini Review discusses the challenges faced, approaches taken and lessons learned in developing a biosimilar rhEPO product, both before and after the publication of the regulatory guidelines.
Evidence for a Role of Paternal Exposures in Developmental Toxicity
Authors: Cordier Sylvaine
Published: September 2010

Abstract:  Experimental evidence from radiation exposure, antimitotic drugs or chemicals such as pesticides or metals does suggest the possibility of transmission of paternally mediated developmental effects across generations. The mechanistic framework is growing with suggestion of transmission of epigenetic modifications as a mechanism alternative to germ‐line mutagenesis. There is also ample experimental evidence for a specific susceptibility of the male embryo to the action of endocrine disrupters. In parallel, interpretation of epidemiological findings regarding effects of well‐characterized paternal exposures, such as ionizing radiation or persistent organic pollutants (dioxins), on intrauterine development remains equivocal. Many epidemiological studies have included paternal exposures as an add‐on to existing studies and focused mainly on birth defects, sex ratio, childhood cancers or spontaneous abortions. Functional alterations such as neurobehavioural parameters or reproductive dysfunction resulting from paternal exposure have been barely studied. Improved knowledge on possible consequences of paternal exposures in future generations is needed and has strong implication in terms of regulation, in the workplace for instance. One may expect human studies to be conducted with a particular focus on male‐mediated developmental toxicity making use of biological markers pertinent to hypothesized mechanisms. Recognition of early determinants of disease onset has led to the setup of a number of mother–child cohorts across the world and careful assessment of paternal exposures should be included in these studies. These cohorts will also have the power to evaluate the specific impact of in utero exposure on a number of endpoints of developmental toxicity in males.
Health Effects of Early Life Exposure to Arsenic
Authors: Vahter Marie
Published: September 2010

Abstract:  Inorganic arsenic is a potent human carcinogen and general toxicant. More than one hundred million people are exposed to elevated concentrations, mainly via drinking water, but also via industrial emissions. Arsenic is metabolized via methylation and reduction reactions, methylarsonic acid and dimethylarsinic acid being the main metabolites excreted in urine. Both inorganic arsenic and its methylated metabolites easily pass the placenta and both experimental and human studies have shown increased risk of impaired foetal growth and increased foetal loss. Recent studies indicate that prenatal arsenic exposure also increases the risk of adverse effects during early childhood. There is a growing body of evidence that the intrauterine or early childhood exposure to arsenic also induces changes that will become apparent much later in life. One epidemiological study indicated that exposure to arsenic in drinking water during early childhood or in utero was associated with an increased mortality in young adults from both malignant and non‐malignant lung disease. Furthermore, a series of experimental animal studies provide strong support for late effects of arsenic, including various forms of cancer, following intrauterine arsenic exposure. The involved modes of action include epigenetic effects, mainly via DNA hypomethylation, endocrine effects (most classes of steroid hormones), immune suppression, neurotoxicity, and interaction with enzymes critical for foetal development and programming.
Pesticide Toxicity and the Developing Brain
Authors: Eskenazi Brenda , Rosas Lisa G. , Marks Amy R. , Bradman Asa , Harley Kim , Holland Nina , Johnson Caroline , Fenster Laura , Barr Dana B.
Published: September 2010

Abstract:  Organochlorine pesticides are used in some countries for malaria control and organophosphate pesticides are widely used in agriculture and in homes. Previous literature documents children's exposure to these chemicals both in utero and during development. Animal studies suggest that many of these chemicals are neurodevelopmental toxicants even in moderate doses, but there are few studies in human beings. Associations of children's pesticide exposure with neurodevelopment from studies being conducted worldwide are summarized. In addition, we present the work of the CHAMACOS study, a longitudinal birth cohort study of Mexican‐American children living in the Salinas Valley of California. In this study, we investigated the relationship of children's neurodevelopment with maternal dichlorodiphenyltrichloroethane and dichlorodiphenyldichloroethylene serum levels, as well as prenatal and child organophosphate urinary metabolite levels. We have examined the association with children's performance on the Brazelton Neonatal Assessment Scales and at 6, 12 and 24 months on the Bayley Scales of Infant Development (mental development and psychomotor development) and mothers report on the Child Behaviour Checklist. We observed a negative association of prenatal dichlorodiphenyltrichloroethane exposure and child mental development. We also observed adverse associations of prenatal but not postnatal organophosphate pesticide exposure with mental development and pervasive developmental disorder at 24 months.
Characterization of the Exposure–Disease Continuum in Neonates of Mothers Exposed to Carcinogens during Pregnancy
Authors: Godschalk Roger W. L. , Kleinjans Jos C. S.
Published: September 2010

Abstract:  The impact of maternal exposure to carcinogens during pregnancy on childhood cancer risk may be especially relevant for genetically susceptible infants. A molecular epidemiological approach, which has the potential to characterize processes between exposure and subsequent health effects in newborns by using biomarkers, is expected to provide valuable information for actually identifying such vulnerable neonates. Therefore, biomarkers of exposure (e.g. levels of cotinine and metals in cord blood), biomarkers of the biologically relevant dose (e.g. DNA and protein adducts) and biomarkers of early effects (e.g. the occurrence of somatic mutations in cord blood) have been studied in relation to birth outcomes. In this MiniReview, the most important data concerning these biomarker studies in relation to potential adverse health effects in neonates will be summarized and will be compared to the outcome of a small study population (59 mother–child pairs) in which all these biomarkers were assessed simultaneously. Overall, it can be concluded that plasma cotinine levels, macromolecule–carcinogen adduct levels and hypoxanthine phosphoribosyltransferase mutant frequencies are increased in cord blood of neonates of mothers who were exposed during pregnancy and their levels correlated with proxies of health effects, such as reduced birth weight. Moreover, DNA damage was found to be the highest in those neonates that carried risk alleles in genes that code for biotransformation enzymes. These results were confirmed in our study, which indicates that it is possible to identify a susceptible subgroup of newborns. In summary, there is a reason for profound concern of genotoxic effects in newborns of exposed mothers.
Animal Models for Probing the Developmental Basis of Disease and Dysfunction Paradigm
Authors: Heindel Jerrold J.
Published: September 2010

Abstract:  There is a major paradigm shift taking place in science that while simple is profound. The new paradigm suggests that susceptibility to disease is set in utero or neonatally as a result of the influences of nutrition and exposures to environmental stressors/toxicants. In utero nutrition and/or in utero or neonatal exposures to environmental toxicants alter susceptibility to disease later in life as a result of their ability to affect the programming of tissue function that occurs during development. This concept, which is still a hypothesis undergoing scientific testing and scrutiny, is called the developmental basis of health and disease. If true, then it says that the focus on disease prevention and intervention must change from the time of disease onset to perhaps decades prior: during the in utero and neonatal period. Perhaps the reason it has been so difficult to link environmental exposure to disease susceptibility is that scientists have been looking at the wrong time! Certainly, not all exposures that result in increased disease or dysfunction occur during development. This paradigm shift just suggests that this is a sensitive window of exposure that should be examined more thoroughly. This overview focuses on animal models for the assessment of this new scientific paradigm and the animal data that now supports it.
Developmental Origins of Health and Disease: New Insights
Authors: Hanson Mark A. , Gluckman Peter D.
Published: September 2010

Abstract:  Epidemiological and animal studies show that small changes in the developmental environment can induce phenotypic changes affecting an individual's responses to their later environment. These may alter the risk of chronic disease such as metabolic syndrome or cardiovascular disease. Recent research shows that animals exposed to such a mismatch between prenatal and postnatal environment develop obesity, reduced activity, leptin and insulin resistance, elevated blood pressure and vascular endothelial dysfunction. Epigenetic processes are involved in such effects, targeted to promoter regions of specific genes in specific tissues. Such fine control of gene expression suggests that the mechanisms have been retained through evolution through their adaptive advantage, rather than representing extreme effects of developmental disruption akin to teratogenesis. There may be adaptive advantage in a developmental cue inducing a phenotypic change in generations beyond the immediate pregnancy, and a range of data that support this concept. In animals, epigenetic effects such as DNA methylation can be passed to successive generations. Environmental toxins, including endocrine disruptors, may induce greater risk of chronic disease, even at low exposure levels, if they affect such normal developmental epigenetic processes. Appropriate interventions may have long‐term multigenerational effects to reduce the risk of chronic disease.
Lifetime Consequences of Combined Maternal Lead and Stress
Authors: Cory‐Slechta Deborah A. , Virgolini Miriam B. , Rossi‐George Alba , Thiruchelvam Mona , Lisek Renata , Weston Douglas
Published: September 2010

Abstract: Elevated lead (Pb) exposure and high stress both target low socio‐economic status populations. Both also act on the hypothalamic–pituitary–adrenal (HPA) axis. Pb disrupts cognition through effects on the mesocorticolimbic dopamine pathway. Stress hormones act on this same pathway via the HPA axis. The fact that Pb and stress are likely interactive risk factors served as the rationale for a series of studies in our laboratory. These demonstrate that stress can modify Pb effects, that Pb can modify stress responsivity, and, notably, that Pb + stress effects can occur in the absence of an effect of either alone in rats. Furthermore, maternal only Pb exposure can permanently alter basal corticosterone levels, stress responsivity (i.e. permanent modification of HPA axis function) and brain catecholamines in offspring of both genders. Interactive effects of Pb + stress are not limited to early development: even Pb exposures initiated post‐weaning alter basal corticosterone and stress responsivity. Outcomes differ in relation to gender, brain region, stressor and time of measurement, making Pb + stress interactions complex. Altered HPA axis function may serve as a mechanism for the behavioural and catecholaminergic neurotoxicity associated with Pb, as well as for the increased incidence of disease and dysfunctions associated with low socio‐economic status. The permanent consequences of maternal only Pb exposure suggest that Pb screening programmes should include pregnant women at risk for elevated Pb exposure, and that stress should be considered as an additional risk factor. Pb + stress effects observed in the absence of either risk factor alone raise questions about the capacity of current hazard identification approaches to adequately identify human health risks posed by neurotoxicants.
Assessing Intrauterine Influences on Offspring Health Outcomes: Can Epidemiological Studies Yield Robust Findings?
Authors: Smith George Davey
Published: September 2010

Abstract:  The influence of factors acting during the intrauterine period on health outcomes of offspring is of considerable research and public health interest. There are, however, methodological challenges in establishing robust causal links, because exposures often act many decades before outcomes of interest, may act before it is evident that women are pregnant and would enter pregnancy birth cohorts, and may also be strongly related to other factors, generating considerable degrees of potential confounding. The degree of confounding can sometimes be estimated by comparing the association between exposures experienced by the mother during pregnancy and outcomes among the offspring with the association of exposures experienced by the father during the pregnancy period and offspring outcomes. If the effects are due to an intrauterine exposure, then maternal exposure during pregnancy should have a clearly greater influence than paternal exposure. A different approach is that of Mendelian randomization, which utilizes genetic variants of known functional effect that can proxy for modifiable exposures. If carried by the mother, these variants would influence the intrauterine environment experienced by her offspring. These genetic variants are stable over time and can be assessed after pregnancy is complete or even after outcomes in the offspring have been observed. The variants would also not generally be related to potential confounding factors. Other epidemiological strategies are briefly reviewed. It is concluded that the naïve acceptance of findings utilizing conventional epidemiological methods in this setting is misplaced.
A New ‘Crowded Uterine Horn’ Mouse Model for Examining the Relationship Between Foetal Growth and Adult Obesity
Authors: Coe Benjamin L. , Kirkpatrick James R. , Taylor Julia A. , Vom Saal Frederick S.
Published: September 2010

Abstract:  Obesity is an increasing health problem, not only in developed countries but also all over the world. In addition to the focus on food intake and energy expenditure, current studies suggest two other important influences on adult body weight: birth weight and postnatal rate of growth. A common procedure in laboratory animal studies to examine the relationship of low birth weight and adult obesity is maternal nutrient restriction, but maternal undernutrition is not the basis for the majority of obese individuals in developed countries. We have thus developed a new mouse model for human obesity referred to as ‘the crowded uterine horn model’. By removing one ovary from a female CD‐1 mouse, the female produces a litter of about 13 pups in one uterine horn, resulting in crowding and a 4‐fold difference in placental blood flow among foetuses in a litter. Restricted placental blood flow results in intrauterine growth restriction (IUGR); these animals show a 2‐fold increase in body weight during the week after weaning, while macrosomial foetuses that go through a very small amount of growth during the same postnatal period. Male mice categorized as IUGR or macrosomic at birth both are obese in adulthood. This pattern of changes in body weight throughout life in male mice mirrors findings from epidemiological studies of human foetuses with IUGR and macrosomia who become obese, and thus may provide a new model that reflects the condition of people in developed countries who become obese.
Testicular Dysgenesis Syndrome and Leydig Cell Function
Authors: Joensen Ulla Nordström , Jørgensen Niels , Meyts Ewa Rajpert‐De , Skakkebæk Niels Erik
Published: September 2010

Abstract:  Fertility among human beings appear to be on the decline in many Western countries, and part of the explanation may be decreasing male fecundity. A hypothesis has been put forward that decreasing semen quality may be associated with a testicular dysgenesis syndrome (TDS), a spectrum of disorders originating in early foetal life. TDS comprises various aspects of impaired gonadal development and function, including testicular cancer. A growing body of evidence, including animal models and research in human beings, points to lifestyle factors and endocrine disrupters as risk factors for TDS. We present our view of the emerging role of Leydig cell dysfunction with subsequent decreased testosterone levels in the pathogenesis of TDS.
Establishing Evidence for Early Action: the Prevention of Reproductive and Developmental Harm
Authors: Gee David
Published: September 2010

Abstract:  Developmental and reproductive toxicants that cause serious disease and dysfunction, either lifelong or occurring late in life, can be initiated in the early life stages of human beings and other species. It is often the timing of the dose more than the dose itself that distinguishes harmful from harmless exposures to such toxicants. As much of the harm is irreversible, and sometimes multigenerational, the timing of actions to prevent such harm is also critical. In determining when there is a sufficiency of evidence to justify early prevention of harm, decision‐makers need to take account of the implications of multicausality, the methodological biases within environmental sciences, and the need to take precautionary, as well as preventive actions to eliminate or reduce exposures. The widely used Bradford Hill causal ‘criteria’ are briefly reviewed in light of multicausality. Reaching agreement between stakeholders on a sufficiency of evidence for early action to reduce exposures to toxicants requires the consistent use of transparent definitions of the concepts and terms used to characterize the strength of evidence between causes and effects. Proposals are made to improve those in current use, including a definition of the precautionary principle.
Effect of Carbamazepine and Lamotrigine on Cognitive Function and Oxidative Stress in Brain during Chemical Epileptogenesis in Rats
Authors: Arora Tarun , Mehta Ashish K. , Sharma Krishna K. , Mediratta Pramod K. , Banerjee Basu D. , Garg Gobind R. , Sharma Amit K.
Published: September 2010

Abstract:  The present study assessed the effect of carbamazepine and lamotrigine on cognitive function and oxidative stress in brain during chemically induced epileptogenesis in rats. Epileptogenesis was induced by administration of pentylenetetrazole (30 mg/kg, s.c.) on alternate days (three times/week) for 9–11 weeks or until stage 4 of seizure score was achieved. The neurobehavioural parameters used for cognitive assessment were step‐down latency in continuous avoidance apparatus and transfer latency in elevated plus maze test paradigm. Carbamazepine and lamotrigine were administered intraperitoneally in doses of 60 mg/kg and 25 mg/kg, respectively, according to the groups, once a day for 11 weeks. Oxidative stress was assessed in isolated homogenized whole brain samples and estimated for the levels of malondialdehyde, reduced glutathione, catalase and superoxide dismutase. The results showed that lamotrigine did not produce any change in cognitive function, while carbamazepine produced cognitive dysfunction. Cognitive decline seen in the carbamazepine‐treated pentylenetetrazole‐kindled group was also associated with increased oxidative stress. Lamotrigine treatment had no effect on oxidative stress parameters alone, while it significantly decreased oxidative stress in the pentylenetetrazole‐kindled group as compared to the pentylenetetrazole‐kindled carbamazepine‐treated group.
Dose‐Dependent Adsorptive Capacity of Activated Charcoal for Gastrointestinal Decontamination of a Simulated Paracetamol Overdose in Human Volunteers
Authors: Gude Anne‐Bolette Jill , Hoegberg Lotte Christine Groth , Angelo Helle Riis , Christensen Hanne Rolighed
Published: September 2010

Abstract:  The amount of activated charcoal needed to treat drug overdoses has arbitrarily been set at a charcoal‐drug ratio of 10:1. Recent in vitro studies have shown a larger adsorptive capacity for activated charcoal when used in a model of paracetamol overdose. In the present study, we investigated whether this reserve capacity exists in vivo. This is clinically relevant in cases of large overdoses or if the full standard dose of 50 g activated charcoal cannot be administered. We performed a randomized, cross‐over study (n = 16). One hour after a standard breakfast, 50 mg/kg paracetamol was administered, followed 1 hr later by an activated charcoal‐Water slurry containing 50 (control), 25 or 5 g activated charcoal. The areas under the serum concentration‐time curve (AUC) for paracetamol were used to estimate the efficacy of each activated charcoal dose. The AUC of the 25‐g dose was found to be of similar size compared to the control, although statistics were weak. The AUC of the 5‐g dose was 59% larger than the AUC of the 50‐g dose (p = 0.0003). The terminal elimination half‐life (t1/2) of paracetamol was 1.6 (CI 1.4–2.0) and 1.9 (CI 1.5–2.4) hr for 50 and 25 g, respectively (NS), and 2.5 (CI 1.8–3.0) hr for the 5‐g dose (p = 0.003). The decrease in t1/2 of paracetamol for the two larger activated charcoal doses indicates a possible effect of activated charcoal on paracetamol clearance and warrants further investigation. The large adsorptive reserve capacity of activated charcoal in vitro could not be reproduced for the smallest dose of activated charcoal. An activated charcoal‐drug ratio of 10:1 is therefore still recommendable.