Boisen, Anne Mette Zenner

Partikler i luftforurening er blevet associeret med en øgning i risiko for kræft og cardiovaskulære sygdomme hos mennesker. Luftforurening kan have en negativ påvirkning på graviditetsparametre og sædcelle-DNA-integritet.Dyrestudier har desuden vist at inhalation af partikelforurening kan inducere mutationer i premeiotiske sædceller. Det er yderst vigtigt at få undersøgt denne potentielle mutationsrisiko da mutationer kan føre til kræft. Arvelige mutationer kan også videreføres til kommende generationer og på den måde udgøre en permanent risiko for genetiske påvirkninger i befolkningen.Der er på det sidste kommet en øget fokus på fraktionen af partikelforurening i nanostørrelse. Inhalerede nanopartikler fjernes langsomt fra lungerne og en lille andel kan muligvis translokere over i blodbanen og videre ud i kroppen. I luftvejene kan nanopartikler generere betændelsestilstande samt oxidativt stress. Nanopartikler er mere reaktive end større partikler og kan have unikke egenskaber på grund af deres lille størrelse. Eksponeringen for nanopartikler i arbejdsmiljøet samt som forbruger vil sandsynligvis stige kraftigt i den nærmeste fremtid og en grundig undersøgelse af deres potentielt skadelige effekter er påkrævet.Ekspanderede simple tandem DNA gentagelser (ESTR) i mus er følsomme markører for mutagene effekter forårsaget af en miljøpåvirkning. Studier på voksne mus har vist, at mens partikelforurening inducerer ESTR mutationer i premeiotiske sædceller, bliver kvindelige kønsceller ikke påvirket. I modsætning til sædceller, som dannes løbende gennem hele voksenlivet befinder størstedelen af ægceller sig i et hvilestadie gennem lange perioder af kvindens liv og ægceller er derfor muligvis mindre følsomme overfor mutationer. Ægceller kan imidlertid være følsomme overfor mutationer under fosterudviklingen, hvor de kvindelige kønsceller udvikles.Formålet med denne PhD var at undersøge om to hyppigt brugte nanopartikler titanium dioxid UV-Titan og carbon black Printex 90 kan inducere ESTR mutationer i prenatalt eksponerede kvindelige kønsceller. Gravide generation P mus blev eksponeret for ~42 mg UV-Titan/m3/1 t/d fra gestationsdag 8-18 eller for carbon black Printex 90 ved gestationsdag (7,10,15 og 18) (total dosis 268 μg/dyr) ved intratracheal instillation. Maternel inflammation og DNA skade blev undersøgt for at vurdere den potentielle indirekte effekt på afkom under graviditeten. Prenatalt eksponerede F1 hunmus blev ved kønsmodning parret med ueksponerede hanmus. ESTR mutationsraten i F2 afkom blev estimeret fra avl af (mor, far, afkom). ESTR mutation rater (0,029/0,0025 for den maternelle allel og 0,047/0,053 for den paternelle allel) for UV-Titan/Printex 90-eksponerede F2 afkom var ikke statistisk signifikant forskellige fra mutationsraterne i F2 kontroller: (0,037/0,024 for den maternelle allel og 0,061/0,038 for den paternelle allel).Eksponering for UV-Titan og Printex 90 inducerede lungeinflammation i gravide generation P mus samt ændringer i genekspressionen i leveren hos F1 prenatalt eksponeret hunligt afkom. Der var i midlertidig ikke nogen ændring i ESTR mutationsraten ved UV-Titan eller Printex 90 eksponering af hunligt F1 afkom i fostertilstanden.Particulate air pollution has been associated with an increased risk of cardiovascular disease and cancer in humans. Air pollution may also adversely affect pregnancy outcome and the integrity of sperm cells DNA. Animal studies have shown that inhalation of air particulates can induce mutations in premeiotic sperm cells. The investigation of potential mutagenic risk is of outmost importance, as it may lead to cancer. Furthermore, heritable mutations may be passed on to descendents and thereby pose a permanent genetic risk to the population.The nanosized fraction of particulate air pollution has recently come into focus. Inhaled nanoparticles are cleared very slowly from the lungs and a small fraction may translocate into the bloodstream and compartments of the body. In the airways nanoparticles can induce a high degree of pulmonary inflammation and oxidative stress. Nanoparticles are more reactive than larger sized particles and may have unique properties as a result of their size. The exposure to nanoparticles in the occupational setting and from consumer products will most likely increase greatly in the near future and thorough investigations of their potentially hazardous effects are needed.Expanded simple tandem repeat (ESTR) loci in mice are sensitive markers of mutagenic effects resulting from environmental exposures; Studies on adult mice have revealed that while particulate air pollution induced ESTR mutations in premeiotic sperm cells, the female germline was not affected. Unlike sperm cells that are continuously developed in adulthood, the majority of oocytes are in a dormant state during long periods of adult life and may therefore be less sensitive to mutations. However, female germ cells may be vulnerable during pregnancy when the female germ cells of the fetus when are actively dividing.The aim of this PhD study was to determine if two widely used nanoparticles titanium dioxide UV-Titan and carbon black Printex 90 induce ESTR mutations in the germ cells of prenatally exposed females. Pregnant generation P mice were exposed to ~42 mg UV-Titan/m3/1 h/d during gestation days 8-18 or carbon black Printex 90 at gestation days (7,10,15 and 18) (total dose of 268 μg/animal) by intratracheal instillation. Maternal inflammation and DNA damage were assessed in order to assess the potential for indirect effects on offspring during pregnancy. Prenatally exposed F1 females were grown to maturity and mated with unexposed males. The ESTR mutation rate in F2 offspring was estimated from full pedigrees (mother, father, offspring). ESTR mutation rates of 0.029/0.0025 (maternal allele) and 0.047/0.053 (paternal allele) in UV-Titan/Printex 90-exposed F2 offspring were not statistically different from those of F2 controls: 0.037/0.024 (maternal allele) and 0.061/0.038 (paternal allele). UV-Titan and Printex 90 exposure induced pulmonary inflammation in pregnant generation P mothers as well as changes in hepatic gene expression in the F1 prenatally exposed females. However, ESTR mutation rates were not increased by UV-Titan or Printex 90 in prenatally exposed F1 females

Online Research Database In Technology

Effects of prenatal exposure to nanoparticles titanium dioxide and carbon black on female germline DNA stability

http://orbit.dtu.dk/ws/files/51143607/Anne_Mette_Zenner_Boisen_Afhandling..PDF

Effects of prenatal exposure to nanoparticles titanium dioxide and carbon black on female germline DNA stability

Abstract

Similar works

Full text

Available Versions

Online Research Database In Technology