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Evolutionary heritage influences amazon tree ecology
Souza, Fernanda Coelho De; Dexter, Kyle G. ; Phillips, Oliver L. ; Brienen, Roel J.W. ; Chave, Jerome ; Galbraith, David R. ; Gonzalez, Gabriela Lopez ; Mendoza, Abel Monteagudo ; Toby Pennington, R. ; Poorter, Lourens ; Arets, E.J.M.M. ; Boot, Rene G.A. ; Meer, Peter J. van der - \ 2016
Proceedings of the Royal Society. B: Biological Sciences 283 (2016)1844. - ISSN 0962-8452
Convergent evolution - Divergent selection - Phylogenetic signal - Trait - Tropical tree
Lineages tend to retain ecological characteristics of their ancestors through time. However, for some traits, selection during evolutionary history may have also played a role in determining trait values. To address the relative importance of these processes requires large-scale quantification of traits and evolutionary relationships among species. The Amazonian tree flora comprises a high diversity of angiosperm lineages and species with widely differing life-history characteristics, providing an excellent system to investigate the combined influences of evolutionary heritage and selection in determining trait variation. We used trait data related to the major axes of life-history variation among tropical trees (e.g. growth and mortality rates) from 577 inventory plots in closed-canopy forest, mapped onto a phylogenetic hypothesis spanning more than 300 genera including all major angiosperm clades to test for evolutionary constraints on traits. We found significant phylogenetic signal (PS) for all traits, consistent with evolutionarily related genera having more similar characteristics than expected by chance. Although there is also evidence for repeated evolution of pioneer and shade tolerant lifehistory strategies within independent lineages, the existence of significant PS allows clearer predictions of the links between evolutionary diversity, ecosystem function and the response of tropical forests to global change.
Phylogenetic diversity of Amazonian tree communities
Honorio Coronado, E.N. ; Dexter, K.G. ; Pennington, R.T. ; Chave, Jérôme ; Lewis, S.L. ; Alexiades, M.N. ; Alvarez, Esteban ; Alves de Oliveira, Atila ; Amaral, J.L. ; Araujo-Murakami, Alejandro ; Arets, E.J.M.M. - \ 2015
Diversity and Distributions 21 (2015)11. - ISSN 1366-9516 - p. 1295 - 1307.
Amazon basin - Eudicots - Magnoliids - Monocots - Phylogenetic diversity - Species richness
Aim: To examine variation in the phylogenetic diversity (PD) of tree communities across geographical and environmental gradients in Amazonia. Location: Two hundred and eighty-three c. 1 ha forest inventory plots from across Amazonia. Methods: We evaluated PD as the total phylogenetic branch length across species in each plot (PDss), the mean pairwise phylogenetic distance between species (MPD), the mean nearest taxon distance (MNTD) and their equivalents standardized for species richness (ses.PDss, ses.MPD, ses.MNTD). We compared PD of tree communities growing (1) on substrates of varying geological age; and (2) in environments with varying ecophysiological barriers to growth and survival. Results: PDss is strongly positively correlated with species richness (SR), whereas MNTD has a negative correlation. Communities on geologically young- and intermediate-aged substrates (western and central Amazonia respectively) have the highest SR, and therefore the highest PDss and the lowest MNTD. We find that the youngest and oldest substrates (the latter on the Brazilian and Guiana Shields) have the highest ses.PDss and ses.MNTD. MPD and ses.MPD are strongly correlated with how evenly taxa are distributed among the three principal angiosperm clades and are both highest in western Amazonia. Meanwhile, seasonally dry tropical forest (SDTF) and forests on white sands have low PD, as evaluated by any metric. Main conclusions: High ses.PDss and ses.MNTD reflect greater lineage diversity in communities. We suggest that high ses.PDss and ses.MNTD in western Amazonia results from its favourable, easy-to-colonize environment, whereas high values in the Brazilian and Guianan Shields may be due to accumulation of lineages over a longer period of time. White-sand forests and SDTF are dominated by close relatives from fewer lineages, perhaps reflecting ecophysiological barriers that are difficult to surmount evolutionarily. Because MPD and ses.MPD do not reflect lineage diversity per se, we suggest that PDss, ses.PDss and ses.MNTD may be the most useful diversity metrics for setting large-scale conservation priorities.
Recently evolved diversity and convergent radiations of rainforest mahoganies (Meliaceae) shed new light on the origins of rainforest hyperdiversity
Koenen, E.J.M. ; Clarkson, J.J. ; Pennington, T.D. ; Chatrou, L.W. - \ 2015
New Phytologist 207 (2015)2. - ISSN 0028-646X - p. 327 - 339.
plastid dna-sequences - plant diversity - molecular phylogenetics - south-america - rapid diversification - evolutionary history - tropical forests - guarea meliaceae - global patterns - east dispersal
•Tropical rainforest hyperdiversity is often suggested to have evolved over a long time-span (the ‘museum’ model), but there is also evidence for recent rainforest radiations. The mahoganies (Meliaceae) are a prominent plant group in lowland tropical rainforests world-wide but also occur in all other tropical ecosystems. We investigated whether rainforest diversity in Meliaceae has accumulated over a long time or has more recently evolved. •We inferred the largest time-calibrated phylogeny for the family to date, reconstructed ancestral states for habitat and deciduousness, estimated diversification rates and modeled potential shifts in macro-evolutionary processes using a recently developed Bayesian method. •The ancestral Meliaceae is reconstructed as a deciduous species that inhabited seasonal habitats. Rainforest clades have diversified from the Late Oligocene or Early Miocene onwards. Two contemporaneous Amazonian clades have converged on similar ecologies and high speciation rates. •Most species-level diversity of Meliaceae in rainforest is recent. Other studies have found steady accumulation of lineages, but the large majority of plant species diversity in rainforests is recent, suggesting (episodic) species turnover. Rainforest hyperdiversity may best be explained by recent radiations from a large stock of higher level taxa.
Fast demographic traits promote high diversification rates of Amazonian trees
Baker, T.R. ; Pennington, R.T. ; Magallon, S. ; Gloor, E. ; Laurance, W.F. ; Alexiades, M. ; Alvarez, E. ; Araujo, A. de; Arets, E.J.M.M. - \ 2014
Ecology Letters 17 (2014)5. - ISSN 1461-023X - p. 527 - 536.
species richness - ecological limits - divergence times - life-history - diversity - evolution - patterns - forests - climate - clades
The Amazon rain forest sustains the world's highest tree diversity, but it remains unclear why some clades of trees are hyperdiverse, whereas others are not. Using dated phylogenies, estimates of current species richness and trait and demographic data from a large network of forest plots, we show that fast demographic traits – short turnover times – are associated with high diversification rates across 51 clades of canopy trees. This relationship is robust to assuming that diversification rates are either constant or decline over time, and occurs in a wide range of Neotropical tree lineages. This finding reveals the crucial role of intrinsic, ecological variation among clades for understanding the origin of the remarkable diversity of Amazonian trees and forests
Towards a new classification system for legumes: Progress report from the 6th International Legume Conference
Pontes Coelho Borges, L.M. ; Bruneau, A. ; Cardoso, D. ; Crisp, M. ; Delgado-Salinas, A. ; Doyle, J.J. ; Egan, A. ; Herendeen, P.S. ; Hughes, C. ; Kenicer, G. ; Klitgaard, B. ; Koenen, E. ; Lavin, M. ; Lewis, G. ; Luckow, M. ; Mackinder, B. ; Malecot, V. ; Miller, J.T. ; Pennington, R.T. ; Queiroz, L.P. de; Schrire, B. ; Simon, M.F. ; Steele, K. ; Torke, B. ; Wieringa, J.J. ; Wojciechowski, M.F. ; Boatwright, S. ; Estrella, M. de la; Mansano, V.D. ; Prado, D.E. ; Stirton, C. ; Wink, M. - \ 2013
South African Journal of Botany 89 (2013). - ISSN 0254-6299 - p. 3 - 9.
caesalpinioid legumes - phylogeny - leguminosae - evolution - diversification - dipsacales - sequences - lineages - gene - rbcl
Legume systematists have been making great progress in understanding evolutionary relationships within the Leguminosae (Fabaceae), the third largest family of flowering plants. As the phylogenetic picture has become clearer, so too has the need for a revised classification of the family. The organization of the family into three subfamilies and 42 tribes is outdated and evolutionarily misleading. The three traditionally recognized subfamilies, Caesalpinioideae, Mimosoideae, and Papilionoideae, do not adequately represent relationships within the family. The occasion of the Sixth International Legume Conference in Johannesburg, South Africa in January 2013, with its theme "Towards a new classification system for legumes," provided the impetus to move forward with developing a new classification. A draft classification, based on current phylogenetic results and a set of principles and guidelines, was prepared in advance of the conference as the basis for discussion. The principles, guidelines, and draft classification were presented and debated at the conference. The objectives of the discussion were to develop consensus on the principles that should guide the development of the classification, to discuss the draft classification's strengths and weaknesses and make proposals for its revision, and identify and prioritize phylogenetic deficiencies that must be resolved before the classification could be published. This paper describes the collaborative process by a large group of legume systematists, publishing under the name Legume Phylogeny Working Group, to develop a new phylogenetic classification system for the Leguminosae. The goals of this paper are to inform the broader legume community, and others, of the need for a revised classification, and spell out clearly what the alternatives and challenges are for a new classification system for the family. (C) 2013 SAAB. Published by Elsevier B.V. All rights reserved.
Legume phylogeny and classification in the 21st century: Progress, prospects and lessons for other species-rich clades
Bruneau, A. ; Doyle, J.J. ; Herendeen, P. ; Hughes, C. ; Kenicer, G. ; Lewis, G. ; Mackinder, B.A. ; Pennington, R.T. ; Sanderson, M.J. ; Wojciechowski, M.F. ; Boatwright, S. ; Brown, G. ; Cardoso, D. ; Crips, M. ; Egan, A. ; Fortunato, R. ; Hawkins, J. ; Kajita, T. ; Klitgaard, B.B. ; Koenen, E. ; Lavin, M. ; Luckow, M. ; Marazzi, B. ; McMahon, M.M. ; Miller, J.T. ; Murphy, D.J. ; Ohashi, H. ; Queiroz, L.P. de; Rico, L. ; Särkinen, T. ; Schrire, B. ; Simon, M.F. ; Souza, E.R. ; Steele, K. ; Torke, B.M. ; Wieringa, J.J. ; Wijk, B.E. - \ 2013
Taxon 62 (2013)2. - ISSN 0040-0262 - p. 217 - 248.
swartzia leguminosae-papilionoideae - tribe millettieae leguminosae - chloroplast dna regions - southern south-america - intron spacer regions - matk coding sequence - plastid trnl-f - molecular phylogenetics - divergence times - s.l. leguminosae
The Leguminosae, the third-largest angiosperm family, has a global distribution and high ecological and economic importance. We examine how the legume systematic research community might join forces to produce a comprehensive phylogenetic estimate for the ca. 751 genera and ca. 19,500 species of legumes and then translate it into a phylogeny-based classification. We review the current state of knowledge of legume phylogeny and highlight where problems lie, for example in taxon sampling and phylogenetic resolution. We review approaches from bioinformatics and next-generation sequencing, which can facilitate the production of better phylogenetic estimates. Finally, we examine how morphology can be incorporated into legume phylogeny to address issues in comparative biology and classification. Our goal is to stimulate the research needed to improve our knowledge of legume phylogeny and evolution; the approaches that we discuss may also be relevant to other species-rich angiosperm clades
“Infectobesity: viral infections (especially with human adenovirus-36: Ad-36) may be a cause of obesity
Ginneken, V.J.T. van; Sitnyakowsky, L. ; Jeffery, J.E. - \ 2009
Medical Hypotheses 72 (2009)4. - ISSN 0306-9877 - p. 383 - 388.
canine-distemper virus - metabolic syndrome - national-health - us adults - prevalence - overweight - adiposity - disease - model - preadipocytes
In recent years viral infections have been recognized as possible cause of obesity, alongside the traditionally recognized causes (genetic inheritance, and behaviour/environmental causes such as diet exercise, cultural practices and stress). Although four viruses have been reported to induce obesity (infectoobesity) in animal models (chickens, mice, sheep, goat, dogs, rats and hamsters), until recently the viral etiology of human obesity has not received sufficient attention, possibly because the four viruses are not able to infect humans. In a series of papers over the last ten years, however, the group of Prof. Dhurandhar (Pennington Biomedical Research Center, LA, USA) demonstrated that a human adenovirus, adenovirus-36 (Ad-36), is capable of inducing adiposity in experimentally infected chickens, mice and non-human primates (marmosets). Ad-36 is known to increase the replication, differentiation, lipid accumulation and insulin sensitivity in fat cells and reduces those cells’ leptin secretion and expression. It also affects human primary preadipocytes. In rats increased adiposity was observed due to Ad-36 infection. Recent studies have shown that, in the USA, antibodies to Ad-36 were more prevalent in obese subjects (30%) than in non-obese subjects (11%). We postulate that Ad-36 may be a contributing factor to the worldwide rising problem of obesity. We suggest the extension of comparative virological studies between North America and Europe, and studies between discordant twins (both dizygous and monozygous)
Do Farmers reduce genetic diversity when they domesticate tropical trees? a case study from Amazonia.
Hollingsworth, P.M. ; Dawson, I.K. ; Goodall-Copestake, W.P. ; Richardson, J.E. ; Weber, J.C. ; Sotelo Montes, C. ; Pennington, R.T. - \ 2005
Molecular Ecology 14 (2005)2. - ISSN 0962-1083 - p. 497 - 501.
conservation - leguminosae - bottlenecks - richness - markers
Agroforestry ecosystems may be an important resource for conservation and sustainable use of tropical trees, but little is known of the genetic diversity they contain. Inga edulis, a widespread indigenous fruit tree in South America, is used as a model to assess the maintenance of genetic diversity in five planted vs. five natural stands in the Peruvian Amazon. Analysis of five SSR (simple sequence repeat) loci indicated lower allelic variation in planted stands [mean corrected allelic richness 31.3 (planted) and 39.3 (natural), P = 0.009]. Concerns regarding genetic erosion in planted Amazonian tree stands appear valid, although allelic variation on-farm is still relatively high
Introduction and synthesis: plant phylogeny and the origin of major biomes
Pennington, R.T. ; Cronk, Q.C.B. ; Richardson, J.E. - \ 2004
Philosophical Transactions of the Royal Society. Series B, Biological Sciences 359 (2004)1450. - ISSN 0962-8436 - p. 1455 - 1464.
estimating divergence times - cape-flora - floristic diversity - molecular evolution - south-america - global 200 - forest - biogeography - speciation - africa
Phylogenetic trees based upon DNA sequence data, when calibrated with a dimension of time, allow inference of: (i) the pattern of accumulation of lineages through time; (ii) the time of origin of monophyletic groups; (iii) when lineages arrived in different geographical areas; (iv) the time of origin of biome-specific morphologies. This gives a powerful new view of the history of biomes that in many cases is not provided by the incomplete plant fossil record. Dated plant phylogenies for angiosperm families such as Leguminoaceae (Fabaceae), Melastomataceae sensu stricto, Annonaceae and Rhamnaceae indicate that long-distance, transoceanic dispersal has played an important role in shaping their distributions, and that this can obscure any effect of tectonic history, previously assumed to have been the major cause of their biogeographic patterns. Dispersal from other continents has also been i mportant in the assembly of the Amazonian rainforest flora and the Australian flora. Comparison of dated biogeographic patterns of plants and animals suggests that recent long-distance dispersal might be more prevalent in plants, which has major implications for community assembly and coevolution. Dated plant phylogenies also reveal the role of past environmental changes on the evolution of lineages in species-rich biomes, and show that recent Plio-Pleistocene diversification has contributed substantially to their current species richness. Because of the critical role of fossils and morphological characters in assigning ages to nodes in phylogenetic trees, future studies must include careful morphological consideration of fossils and their extant relatives in a phylogenetic context. Ideal study systems will be based upon DNA sequence data from multiple loci and multiple fossil calibrations. This allows cross-validation both of age estimates from different loci, and from different fossil calibrations. For a more complete view of biome history, future studies should emphasize full taxon sampling in ecologically important groups, and should focus on geographical areas for which few species-level phylogenies are available, such as tropical Africa and Asia. These studies are urgent because understanding the history of biomes can both inform conservation decisions, and help predict the effects of future environmental changes at a time when biodiversity is being impacted on an unprecedented scale
Interactions of polyhalogenated aromatic hydrocarbons with thyroid hormone metabolism
Schuur, A.G. - \ 1998
Agricultural University. Promotor(en): Peter van Bladeren; T.J. Visser; A. Brouwer. - S.l. : Schuur - ISBN 9789054859406 - 173 p.
gechloreerde koolwaterstoffen - schildklierhormonen - chlorinated hydrocarbons - thyroid hormones
<p>This thesis deals with the possible interactions of polyhalogenated aromatic hydrocarbons and/or their metabolites with thyroid hormone metabolism. This chapter summarizes firstly the effects of thyroid hormone on the induction of biotransformation enzymes by PHAHs. Secondly, the results on the inhibition of thyroid hormone sulfation by hydroxylated metabolites of PHAH are summarized. Some conclusions and remarks on the overall implications of the results are given at the end of this chapter.</p><p><strong>The effects of thyroid hormone on the induction of biotransformation enzymes by polyhalogenated aromatic hydrocarbons</strong><br/>The first part of this thesis focussed on the question whether or not the PHAH-induced decrease of plasma T4 is an adaptive endocrine response of the animal to cope with the onset of toxic effects by PHAHs. For this purpose, the possible regulatory effect of thyroid hormones on biotransformation enzymes was investigated, using rats differing in thyroid state which were exposed to TCDD or PCBs as model inducers of biotransformation enzymes.</p><p>In <em>Chapter 2</em> , the thyroid state of euthyroid (Eu), thyroidectomized (Tx) and Tx rats in which T3 or T4 levels are restored using osmotic minipumps were compared. The decreased circulatory levels of plasma T4 and T3, the increased pituitary feedback response (plasma TSH levels), as well as changed functional responses (decreased hepatic D1 and malic enzyme activities, and increased brain D2 activities) in Tx rats were largely restored to Eu levels in Tx+T4 rats and, except for plasma TT4 and brain D2 activity, in Tx+T3 rats. These results indicated that the thyroid hormone-replaced Tx rats were valid models to study peripheral effects of TCDD. Three days after exposure to 10 mg TCDD/kg body weight, plasma TT4 and FT4 levels were significantly reduced in Eu rats and in Tx+T4 rats, and plasma T3 was significantly reduced in Tx+T3 but not in Eu or Tx+T4 rats. Hepatic T4 UGT activity was induced by TCDD while T3 UGT activity was only slightly increased in the different exposed groups. These results strongly suggest that the thyroid hormone-decreasing effects of TCDD are predominantly extrathyroidal and mediated by the marked induction of hepatic T4 UGT activity.</p><p>The effects of thyroid state modulation on the induction of detoxification enzymes by TCDD in experimental animals are described in <em>Chapter 3</em> . In all rats, TCDD largely induced CYP1A1/1A2 activity (EROD), CYP1A1 protein content, and CYP1A1 mRNA levels. TCDD exposure also resulted in higher total hepatic cytochrome P450 content, hepatic p-nitrophenol UGT activity, and GST 1-1 protein levels, but had no effect on hepatic NADPH cytochrome P450 reductase activity, overall GST activity and GST 2-2, 3-3, and 4-4 protein levels and iodothyronine sulfotransferase activity. Thyroid state did not affect the total cytochrome P450, and GST activity and protein levels, but slightly decreased CYP1A1/2 activity, NADPH cytochrome P450 reductase activity, PNP UGT activity and iodothyronine sulfotransferase activity were demonstrated in Tx rats, as compared to Eu rats.</p><p>In the second animal experiment, the interaction between thyroid state and PCBs in the regulation of CYP1A1 and CYP2B expression is described ( <em>Chapter 4</em> ). Male Tx Sprague-Dawley rats, Eu rats, and rats made hyperthyroid by infusing T3 were treated with a single ip dose of the CYP2B inducer PCB 153 and the CYP1A inducer PCB 126. The thyroid states of the rats were confirmed by measurement of plasma T4, T3 and TSH and of functional parameters such as hepatic D1 activity, malic enzyme activity and a-glycerolphosphate dehydrogenase activity. Total hepatic cytochrome P450 content was increased by PCB treatment in all groups, but was not affected by thyroid state. NADPH cytochrome P450 reductase activity was decreased in Tx rats and increased in hyperthyroid rats, while PCB treatment had no effect. PCB 126 specifically induced T4 UGT activity, measured in the absence of detergent, and CYP1A activity, protein and mRNA levels, whereas PCB 153 induced T4 UGT activity, measured in the presence of the detergent Brij 56, and CYP2B activity, protein and mRNA levels. Thyroid state, neither hypo nor hyper, significantly affected T4 UGT activity or CYP1A and CYP2B activities, protein or mRNA levels.</p><p>The almost complete lack of response of basal and PCB- or TCDD-induced activities of biotransformation enzymes to changes in thyroid state observed in our studies is in contrast to effects published by others (Kato and Takahashi <em>et al.</em> , 1968; Rumbaugh <em>et al.</em> , 1978; Leakey <em>et al.</em> , 1982; Müller <em>et al.</em> , 1983a/b; Skett, 1987; Yamazoe <em>et al.</em> , 1989; Arlotto and Parkinson, 1989; Murayama et al., 1991; Chowdhury <em>et al.</em> , 1983; Moscioni and Gartner, 1983; Pennington <em>et al.</em> , 1988; Goudonnet <em>et al.</em> , 1990; Williams <em>et al.</em> , 1986; Pimental <em>et al.</em> , 1993). This may be due to differences in strain and sex of the animals, the severity and duration of the hypo- and hyperthyroid states induced as well as the duration and dose of TCDD/PCB treatment. Overall, it can be concluded that hepatic NADPH cytochrome P450 reductase activity is dependent on thyroid state, whereas total cytochrome P450 as well as CYP1A1 and CYP2B together with UGT, GST and sulfotransferase activities show little or no thyroid hormone dependence. These slight effects are unlikely to represent an endocrine adaptation to a chemical stressor (TCDD). Therefore, the PHAH-induced decreased T4 levels , as well as other aspects of PHAH-induced alterations in thyroid hormone metabolism, are most likely a direct reflection of the developing toxicological response of the animals toward PHAH exposure.</p><p><strong>Inhibition of thyroid hormone sulfation by hydroxylated metabolites of polyhalogenated aromatic hydrocarbons</strong><br/>The second part of this thesis focussed on the question whether or not hydroxylated metabolites of PHAHs (PHAH-OHs) are able to inhibit thyroid hormone sulfation <em>in vitro</em> as well as <em>in vivo</em> .</p><p><em>Chapter 5</em> presents the investigations concerning the possible inhibitory effects of PHAH-OHs on iodothyronine sulfotransferase (SULT) activity. Rat liver cytosol was used as a source of sulfotransferase in an <em>in vitro</em> assay with <sup>125</SUP>I-labelled T2 as a model substrate. Hydroxylated metabolites of PCBs, PCDDs and PCDFs were found to be potent inhibitors of T2 SULT activity <em>in vitro</em> with IC50 values in the low micromolar range (0.2-3.8 mM). The most potent inhibitor of T2 SULT activity within our studies was the PCB metabolite 3-hydroxy-2,3',4,4',5-pentachlorobiphenyl with an IC50 value of 0.2 mM. A hydroxyl group in the para or meta position appeared to be an important structural requirement for T2 SULT inhibition by PCB metabolites. Ortho hydroxy PCBs were much less potent and none of the parent PHAHs were capable of inhibiting T2 SULT activity. In addition, the formation of T2 SULT-inhibiting metabolites from individual brominated diphenyl ethers and nitrofen as well as from some commercial PHAH mixtures (e.g. Bromkal, Clophen A50 and Aroclor 1254) by CYP450 catalyzed hydroxylation was also demonstrated.</p><p>Consequently, the inhibition of thyroid hormone sulfation by PHAH-OHs was studied in more detail, investigating isozyme specificity and inhibition kinetics ( <em>Chapter 6</em> ). The difference in inhibition pattern demonstrated for SULT activity present in rat liver and brain cytosol, is probably caused by a difference in isozyme pattern. It was shown that PCB-OHs inhibited T2 sulfation by interacting with the rat isozyme SULT1C1 and an additional isozyme responsible for T2 sulfation in female liver cytosol, probably rat SULT1B1, but not SULT1A1. On the other hand, human phenol SULT1A1 was inhibited by PCB-OHs, but not the human isozyme SULT1A3. In conclusion, we suggested that at least human SULT1A1, and rat SULT1C1 and perhaps rat SUL1B1 are involved in the inhibition of T2 sulfation by PCB-OHs. However, more information is needed about the various isozymes involved in iodothyronine sulfation in humans as well as in rats, before definite conclusions can be drawn.</p><p>Furthermore, it is shown that T2 is a good model substrate for the active hormone T3 when investigating the inhibition of thyroid hormone sulfation by hydroxylated metabolites of PHAHs. The inhibition kinetics strongly suggested that the nature of the T2 sulfation inhibition by PCB-OHs is competitive. To obtain more decisive information, tests with purified isozymes should be performed. It was also demonstrated that PCDD-OHs and PCB-OHs themselves are substrates -albeit poor- for SULT enzymes, which further supports the competitive inhibition of thyroid hormone sulfation by PHAH-OHs.</p><p>To bridge the gap between <em>in vitro</em> experiments using cytosol and the <em>in vivo</em> situation, we investigated the inhibition of thyroid hormone sulfation in hepatoma cell lines ( <em>Chapter 7</em> ). Two PCB-OHs, 4-hydroxy-2',3,3',4',5-pentachlorobiphenyl and 4-hydroxy-3,3',4',5-tetrachlorobiphenyl, together with the known sulfation inhibitor pentachlorophenol (PCP) were tested in the rat hepatoma cell line FaO and the human hepatoma cell line HepG2. PCP inhibited T2 sulfation <em>in vitro</em> in FaO and HepG2 cells, although it was 1000 times less potent in whole cells than in rat liver cytosol. Micromolar concentrations of the two tested PCB-OHs hardly affected T2 conjugation in FaO cells, but reduced T2 sulfate formation in HepG2 cells. Inhibition of T2 sulfation was more pronounced using medium without FCS than in medium with 5% FCS, due to a lower uptake of inhibitor by the cells in the presence of serum, as demonstrated using radiolabeled PCP.</p><p>These <em>in vitro</em> results indicate that hydroxylated PHAHs are potent inhibitors of thyroid hormone sulfation. Since thyroid hormone sulfation may play an important role in regulating "free" hormone levels in the fetus, and hydroxylated PCB metabolites are known to accumulate in fetal tissues after maternal exposure to PCBs, these observations <em>in vitro</em> might have implications for fetal thyroid hormone homeostasis and development.</p><p>The <em>in vivo</em> experiment in which was tested if PHAH-OHs are able to inhibit T2 sulfation, was described in <em>Chapter 8</em> . Pregnant rats were exposed to 25 mg Aroclor 1254/kg body weight or to the well-known phenol sulfation inhibitor PCP (25 mg/kg body weight) from day 10 till day 18 of gestation. Fetuses and dams were sacrificed on gestation day 20 (GD20). PCP and PCB metabolite levels in fetal serum and tissues were high. Aroclor 1254, but not PCP exposure resulted in an induction of hepatic EROD and T4 UGT activity in dams.</p><p>PHAHs are known for their disrupting effects on thyroid hormone metabolism, as shown in Figure 9.1. In this animal experiment, Aroclor 1254 exposure caused an increase in T4 UGT activity, resulting in decreased TT4 levels. Treatment with PCP also resulted in decreased serum TT4 levels, but increased FT4 levels, in dams and fetuses. The ratio FT4/TT4 was increased indicating a reduced plasma TTR binding capacity in fetuses and dams following both treatments. D1 activity in liver decreased in dams and fetuses after treatment with Aroclor 1254 and PCP. This decrease is probably caused indirectly by the lowered T4 levels. D2 activity in brain decreased by exposure to PCP in dams but no effect was found in fetuses, and increased by exposure to Aroclor 1254 in fetuses, with no effect in dams. The increasing D2 activity is a response of the brain to low T4 levels, to maintain the T3 homeostasis.</p><p>The positive control PCP was shown to increase the T2 SULT activity measured in maternal liver and brain cytosol. Studies using varying T2 concentrations and different protein concentrations suggested competitive inhibition of PCP carried over in the <em>in vitro</em> assay as well as true induction of T2 SULT activity. This effect of PCP on thyroid hormone sulfation <em>in vivo</em> apparently did not result in lower levels of the product T4S, since fetal and maternal serum levels of T4S were not changed after treatment with PCP. This negative answer may be explained by an increased availability of substrate (FT4; maternal) together with a reduced D1 activity by PCP treatment, resulting in a reduced enzymatic breakdown of T4S.</p><p>Exposure to Aroclor 1254, which resulted in the formation of hydroxylated metabolites, did not significantly change the T2 SULT activity in maternal or fetal brain or liver cytosol, nor the serum levels of T4S.</p><p>Remarkably, the T3S and T4S levels were very low in fetal rat serum in this study, especially when compared with the reported high iodothyronine sulfate levels in fetal human and sheep serum. This can not be explained by low SULT activity levels or high D1 activity levels in rat fetuses on day 20.</p><p><strong>Overall implications of the observed PHAH effects on thyroid hormone metabolism</strong><br/>PHAHs induce a wide spectrum of toxic effects in rats. Some effects have been suggested to be linked to a hypothyroid situation, such as the "wasting syndrome", decreased feed intake, and increased cholesterol concentrations. Indeed, reduced serum T4 concentrations have been observed following exposure to PHAHs (Bastomsky <em>et al.</em> , 1977; Gorski and Rozman, 1987; Hermansky <em>et al.</em> , 1988; Brouwer, 1989; Beetstra <em>et al.</em> , 1991), and it is tempting to speculate about a relationship between the hypothyroxinemia and the observed toxic responses. However, induction of a hypothyroid situation or a hypothyroxinemia by PHAHs could also be regarded as an adaptive endocrine response to diminish the PHAH-induced toxicity. One argument in support of this interpretation is the observed protective effect of thyroidectomy on TCDD-induced lethality and immune toxicity (Rozman <em>et al.</em> , 1985).</p><p>In this study, it is proposed that the T4 decrease could well have a regulatory role in the induction of hepatic biotransformation enzymes, as was reported before (see <em>Chapter 1</em> ). The present investigations suggest that the lowering effects of PHAHs on T4 levels are only a toxic effect of PHAHs and not an adaptive response to regulate the induction of biotransformation enzymes. The differences with other reports on modulating effects of thyroid hormone state on biotransformation enzymes may be explained by differences in the time and dose of inducers as well as by a difference in hypo- or hyperthyroid state. Nevertheless, the T4 decreases in the hypothyroid animals in our study are similar to the PHAH-induced T4 decreases. Therefore, the model was good enough to investigate our hypothesis.</p><p>The second part of this thesis demonstrated that the sulfotransferase enzyme is another thyroid hormone-binding protein, besides D1 and TTR, which can be competitively inhibited by hydroxylated metabolites of PHAHs. In a relatively narrow range of low micromolar concentrations, PHAH-OHs were able to competitively inhibit T2 SULT acttivity <em>in vitro</em> , in a SULT isozyme and tissue specific manner.</p><p>Studies using a perinatal exposure setup were performed to test inhibition of T2 sulfation <em>in vivo</em> . It was demonstrated that the well-known sulfation inhibitor PCP was able to indeed competively inhibit T2 SULT activity, but also was able to upregulate the sulfotransferase protein amounts. Aroclor 1254 exposure resulted in a slight inhibition of T2 SULT activity, probably caused by hydroxylated metabolites formed. This inhibition, together with lower substrate (FT4) levels found after Aroclor treatment did not result in decreased serum T4S levels, which is probably caused by a concomitantly decreased inactivation route, i.e. a decreased D1 activity, together with a higher availibility of substrate (FT4) after PCP exposure.</p><p>Remarkably, the serum T4S levels in fetal rat are low compared to the levels in sheep and human fetal serum samples (Wu <em>et al.</em> , 1992a/b; 1993a/b; Santini <em>et al.</em> , 1993). This could not be explained by already higher D1 activities or a relatively low sulfation activity in the control fetus around GD20. For this reason, we concluded that the fetal rat probably is not a very good model for humans in terms of investigating the impact of toxic compounds on fetal thyroid hormone sulfation. However, it should be mentioned that, although PHAHs and their metabolites interfere at many sites with thyroid hormone transport and metabolism, the fetus apparently is able to cope with those changes and can keep its homeostasis in T3.</p><p>Another interesting point deduced from this study, is that PCP, which could be a model for PCB-OHs, itself showed effects on thyroid hormone levels and metabolism, indicating the importance of phenolic organohalogens compounds for disrupting effects on the thyroid hormone system. This also indicates that the disrupting effects of PCBs on the thyroid hormone system are for a large part caused by the hydroxylated metabolites formed. The own toxicity of PCB-OHs and related phenolic organohalogens inducing a separate set of effects together with the recently observed high fetal accumulation of hydroxy-PHAHs, give reason to further investigate the potential toxicity of these compounds on thyroid hormone metabolism and transport (see also Figure 9.1). It is worth mentioning that besides the "old" organohalogen pollutants that have been phased out since the 1980's, there is a wide range of new products on the market, such as brominated diphenylethers (PBDEs), chlorinated benzenes, bisphenol A and so on. PBDEs, which are nowadays used as flame retardants, have been demonstrated at increasing levels in our environment (De Boer <em>et al.</em> , 1989; Sellstrom <em>et al.</em> , 1996), and are probably able to cause similar effects as PHAHs. Serum T4 decreases have already been reported in rats after exposure to PBDEs (Darnerud <em>et al.</em> , 1996) or PCDEs (Rosiak <em>et al.</em> , 1997). Also, hydroxylated metabolites of PBDEs have been found to competitively inhibit the T4 binding to TTR <em>in vitro</em> (Meerts <em>et al.</em> , 1998).</p><p>The human diet contains a diverse spectrum of naturally occuring and xeno-compounds that affect thyroid hormone metabolism. These include the organohalogens and related contaminants, and in addition, a large number of food components. Flavones and flavonoids have been reported to interfere with thyroid hormone binding proteins such as D1 (Auf'mkolk <em>et al.</em> , 1986; Cody <em>et al.</em> , 1989) and TTR (Lueprasitsakul <em>et al.</em> , 1990; Köhrle <em>et al.</em> , 1986). Flavonoids such as quercetin were similarly found to be able to inhibit phenol sulfotransferase activity <em>in vitro</em> (Walle <em>et al.</em> , 1995; Eaton <em>et al.</em> , 1996), and also other food additives were potent inhibitors of phenol sulfation (Bamforth <em>et al.</em> , 1993). The potential adverse human health impact of these compounds depends on a number of factors, including dietary intake, metabolism and pharmacokinetics, compound potency, serum concentrations, relative binding to serum proteins, and interactions or cross-talk with other endocrine pathways. In a risk evaluation, it should be taken into account that humans are exposed to a mixture of compounds with effects on thyroid hormone metabolism. If the mechanism of interference is similar for all these classes of compounds, the effects might very well be additive, or interactive. Additionally, the very persistent PHAHs are probably of more importance from a risk assessment point of view than the natural food components having a higher degradation rate.</p><p>The effects of PHAHs on the thyroid hormone system in this study have been obtained in rats, are the results relevant for the human situation. Occupational or accidental exposure to high levels of PCBs or PBBs results in changes in serum T4 levels as was found by Bahn <em>et al.</em> (1980), Kreiss <em>et al.</em> (1982), Murai <em>et al.</em> (1987), and Emmet <em>et al.</em> (1988). Moreover, in pregnant women exposed to background levels of PHAHs mainly through diet, a significant negative correlation was observed between human milk levels of PHAHs and plasma T4 and T3 levels (Koopman-Esseboom <em>et al.</em> , 1994). In addition, increases in plasma TSH and both increases and decreases in plasma T4 levels were found in newborn babies following exposure to increasing PHAH levels through in utero and lactational transfer (Pluim <em>et al.</em> , 1993; Koopman-Esseboom <em>et al.</em> , 1994). Besides, prenatal exposure to PCBs is related to disorders in neurological development of children, found in some in epidemiologic studies (Rogan <em>et al.</em> , 1986; Jacobson <em>et al.</em> , 1990). It still is however not clear if these effects of PHAHs on thyroid hormone levels and metabolism may have possible effects on (brain) development.</p>
|Individual fatty acid effects on plasma lipids.
Jonnalagadda, S.S. ; Yu, S. ; Katan, M.B. ; Zock, P.L. ; Kris-Etherton, P.M. - \ 1996
In: Pennington Center Nutrition Series. Vol.6: Nutrition, genetics and heart disease / Bray, G.A., Ryan, D.H., Baton Rouge : Louisiana State Univ. Press - p. 75 - 97.
Dietary trans fatty acids and serum lipoproteins.
Mensink, R.P. ; Zock, P.L. ; Katan, M.B. ; Hornstra, G. - \ 1996
In: Pennington Center Nutrition Series. Vol.6: Nutrition, genetics and heart disease / Bray, G.A., Ryan, D.H., Baton Rouge : Louisiana State Univ. Press - p. 98 - 109.
|Hypo and hyperresponsiveness to diet.
Katan, M.B. - \ 1996
In: Pennington Center Nutrition Series. Vol.6: Nutrition, genetics and heart disease / Bray, G.A., Ryan, D.H., Baton Rouge : Louisiana State Univ. Press - p. 110 - 121.