Toxicokinetic-toxicodynamic modelling of survival of Gammarus pulex in multiple pulse exposures to propiconazole: model assumptions, calibration data requirements and predictive power

Toxicokinetic-toxicodynamic (TKTD) models quantify the time-course of internal concentration, which is defined by uptake, elimination and biotransformation (TK), and the processes which lead to the toxic effects (TD). TKTD models show potential in predicting pesticide effects in fluctuating concentrations, but the data requirements and validity of underlying model assumptions are not known. We calibrated TKTD models to predict survival of Gammarus pulex in propiconazole exposure and investigated the data requirements. In order to assess the need of TK in survival models, we included or excluded simulated internal concentrations based on pre-calibrated TK. Adding TK did not improve goodness of fits. Moreover, different types of calibration data could be used to model survival, which might affect model parameterization. We used two types of data for calibration: acute toxicity (standard LC50, 4 d) or pulsed toxicity data (total length 10d). The calibration data set influenced how well the survival in the other exposure scenario was predicted (acute to pulsed scenario or vice versa). We also tested two contrasting assumptions in ecotoxicology: stochastic death and individual tolerance distribution. Neither assumption fitted to data better than the other. We observed in 10-d toxicity experiments that pulsed treatments killed more organisms than treatments with constant concentration. All treatments received the same dose, i.e. the time-weighted average concentration was equal. We studied mode of toxic action of propiconazole and it likely acts as a baseline toxicant in G. pulex during 10-days of exposure for the endpoint surviva

Early Maternal Alcohol Consumption Alters Hippocampal DNA Methylation, Gene Expression and Volume in a Mouse Model

The adverse effects of alcohol consumption during pregnancy are known, but the molecular events that lead to the phenotypic characteristics are unclear. To unravel the molecular mechanisms, we have used a mouse model of gestational ethanol exposure, which is based on maternal ad libitum ingestion of 10% (v/v) ethanol for the first 8 days of gestation (GD 0.5-8.5). Early neurulation takes place by the end of this period, which is equivalent to the developmental stage early in the fourth week post-fertilization in human. During this exposure period, dynamic epigenetic reprogramming takes place and the embryo is vulnerable to the effects of environmental factors. Thus, we hypothesize that early ethanol exposure disrupts the epigenetic reprogramming of the embryo, which leads to alterations in gene regulation and life-long changes in brain structure and function. Genome-wide analysis of gene expression in the mouse hippocampus revealed altered expression of 23 genes and three miRNAs in ethanol-exposed, adolescent offspring at postnatal day (P) 28. We confirmed this result by using two other tissues, where three candidate genes are known to express actively. Interestingly, we found a similar trend of upregulated gene expression in bone marrow and main olfactory epithelium. In addition, we observed altered DNA methylation in the CpG islands upstream of the candidate genes in the hippocampus. Our MRI study revealed asymmetry of brain structures in ethanol-exposed adult offspring (P60): we detected ethanol-induced enlargement of the left hippocampus and decreased volume of the left olfactory bulb. Our study indicates that ethanol exposure in early gestation can cause changes in DNA methylation, gene expression, and brain structure of offspring. Furthermore, the results support our hypothesis of early epigenetic origin of alcohol-induced disorders: changes in gene regulation may have already taken place in embryonic stem cells and therefore can be seen in different tissue types later in life.Peer reviewe

Vertaisryhmämentorointi-työpajan kehittäminen osana innovaatioprojektia

Tein opinnäytetyöni tutkimuksellisen kehittämistyön otteella, jonka tarkoituksena oli kehittää Metropolia ammattikorkeakoulun ja Espoon seudun koulutuskuntayhtymän Omnian yhteistyössä toteutettuun monialaisen ja moniasteisen Superteam-innovaatioprojektiin vertaisryhmämentoroinnin työvälinettä. Tavoitteena opinnäytetyöllä oli kerätä tietoa innovaatioprojektiin osallistuvien opiskelijoiden kokemuksia vertaisryhmämentoroinnista työvälineenä. Opinnäytetyöhön kerätyn aineiston avulla selvitettiin toimiko KerToi-menetelmän pohjalta sovellettu vertaisryhmämentorointi- työpaja tässä konseptissa. Verme-työpajat suunniteltiin keväällä 2017 toteutetun Superteam-innovaatioprojektissa esiin nousseen tarpeen vastaamiseksi. Superteam-innovaatioprojektissa mukana olleet opettajat koulutettiin verme-työpajojen mentoreiksi ja he toteuttivat verme-työpajan yhteisen suunnitelman mukaisesti. Verme-työpajoissa opiskelijoita 14-18 ryhmästä riippuen. Verme-työpajojen toteutuksen jälkeen kerättiin avointa palautetta osallistuneilta opiskelijoilta ja aineisto analysoitiin induktiivisella sisällön analyysillä. Yhteensä palautetta saatiin 41 opiskelijalta. Aineisto jaettiin sisällöstä nousseiden teemojen mukaan ja niitä tarkasteltiin positiivisen, negatiivisen ja rekantavan palautteen mukaan, jotta verme-työpaja toimintaa voidaan kehittää edelleen toimivaksi kokonaisuudeksi Superteam-innovaatioprojektin toimintamalliksi. Aineistossa keskeiseksi nousi keskustelevan toiminnan merkitys verme-työpajassa, jossa dialoginen ote korostui. Verme-työpajoissa toteutetut tehtävät tulee suunnitella kohderyhmä tarkasti huomioiden, jotta ne vastaavat tarkoitustaan. Mentorin luomalla positiivisella ja moninaisuuden huomioivalla ilmapiirillä oli opiskelijoita toimintaan motivoiva vaikutus. Verme- työpajat tukevat opiskelijan omaa sekä tiimin reflektointia tasavertaisen ja avoimen keskustelun kautta. Verme-työpajat toimivat tässä konseptissa parhaiten integroituna osana muuta Superteam-innovaatioprojektin toimintaa. Kehittämiskohteena opiskelijoiden verme-työpajan lisäksi olisi hyvä olla verme-työpaja projektin mentori-ohjaajille

Importance of Toxicokinetics for lnterspecies Variation in Sensitivity to Chemicals

Interspecies variation in sensitivity to synthetic chemicals can be orders of magnitude large. Species traits causing the variation can be related to toxicokinetics (uptake, distribution, biotransformation, elimination) or toxicodynamics (interaction with biological target sites). We present an approach to systematically measure and model the contribution of uptake, biotransformation, internal distribution, and elimination kinetics toward species sensitivity differences. The aim is to express sensitivity as target tissue specific, internal lethal concentrations. A case study with the pesticides diazinon, imidacloprid, and propiconazole and the aquatic invertebrates Gammarus pulex, Gammarus fossarum, and Lymnaea stagnalis illustrates the approach. L. stagnalis accumulates more pesticides than Gammaridae when measured in whole organisms but less in target tissues such as the nervous system. Toxicokinetics, i.e. biotransformation and distribution, explain the higher tolerance of L. stagnalis to the insecticide diazinon when compared to Gammaridae. L. stagnalis was again more tolerant to the other neurotoxicant imidacloprid; however, the difference in sensitivity could not be explained by toxicokinetics alone, indicating the importance of toxicodynamic differences. Sensitivity to propiconazole was comparable among all species and, when expressed as internal lethal concentrations, falls in the range of baseline toxicity

The Insecticide Imidacloprid Causes Mortality of the Freshwater Amphipod Gammarus pulex by Interfering with Feeding Behavior

If an organism does not feed, it dies of starvation. Even though some insecticides which are used to control pests in agriculture can interfere with feeding behavior of insects and other invertebrates, the link from chemical exposure via affected feeding activity to impaired life history traits, such as survival, has not received much attention in ecotoxicology. One of these insecticides is the neonicotinoid imidacloprid, a neurotoxic substance acting specifically on the insect nervous system. We show that imidacloprid has the potential to indirectly cause lethality in aquatic invertebrate populations at low, sublethal concentrations by impairing movements and thus feeding. We investigated feeding activity, lipid content, immobility, and survival of the aquatic arthropod Gammarus pulex under exposure to imidacloprid. We performed experiments with 14 and 21 days duration, both including two treatments with two high, one day pulses of imidacloprid and one treatment with a low, constant concentration. Feeding of G. pulex as well as lipid content were significantly reduced under exposure to the low, constant imidacloprid concentration (15 mu g/L). Organisms were not able to move and feed - and this caused high mortality after 14 days of constant exposure. In contrast, feeding and lipid content were not affected by repeated imidacloprid pulses. In these treatments, animals were mostly immobilized during the chemical pulses but did recover relatively fast after transfer to clean water. We also performed a starvation experiment without exposure to imidacloprid which showed that starvation alone does not explain the mortality in the constant imidacloprid exposure. Using a multiple stressor toxicokinetic-toxicodynamic modeling approach, we showed that both starvation and other toxic effects of imidacloprid play a role for determining mortality in constant exposure to the insecticide

Importance of Toxicokinetics for Interspecies Variation in Sensitivity to Chemicals

Interspecies variation in sensitivity to synthetic chemicals can be orders of magnitude large. Species traits causing the variation can be related to toxicokinetics (uptake, distribution, biotransformation, elimination) or toxicodynamics (interaction with biological target sites). We present an approach to systematically measure and model the contribution of uptake, biotransformation, internal distribution, and elimination kinetics toward species sensitivity differences. The aim is to express sensitivity as target tissue specific, internal lethal concentrations. A case study with the pesticides diazinon, imidacloprid, and propiconazole and the aquatic invertebrates <i>Gammarus pulex</i>, <i>Gammarus fossarum</i>, and <i>Lymnaea stagnalis</i> illustrates the approach. <i>L. stagnalis</i> accumulates more pesticides than Gammaridae when measured in whole organisms but less in target tissues such as the nervous system. Toxicokinetics, i.e. biotransformation and distribution, explain the higher tolerance of <i>L. stagnalis</i> to the insecticide diazinon when compared to Gammaridae. <i>L. stagnalis</i> was again more tolerant to the other neurotoxicant imidacloprid; however, the difference in sensitivity could not be explained by toxicokinetics alone, indicating the importance of toxicodynamic differences. Sensitivity to propiconazole was comparable among all species and, when expressed as internal lethal concentrations, falls in the range of baseline toxicity

Calibration of the starvation model.

<p>The table shows the calibrated parameter values and their standard deviation.</p

Mean percentage error (%) of individual tolerance (IT) and stochastic death (SD) model when pulsed (PT), constant (CT), or all data was used for calibration of the survival model for <i>Gammarus pulex</i> exposed to imidacloprid.

1<p>Pulsed treatment with a short interval in uncontaminated water between imidacloprid pulses.</p>2<p>Pulsed treatment with a long interval in uncontaminated water between imidacloprid pulses.</p

Feeding activity of <i>Gammarus pulex</i> under constant (treatment C) or pulsed (treatments A and B) exposure to imidacloprid.

1<p>Pulsed treatment with a short interval in uncontaminated water between imidacloprid pulses (4 days).</p>2<p>Pulsed treatment with a long interval in uncontaminated water between imidacloprid pulses (8 days).</p>3<p>Pulsed treatment with a long interval in uncontaminated water between imidacloprid pulses (11 days).</p>4<p>Between control and treatment.</p>5<p>Among all treatments within one experiment.</p