A atividade da serotonina (5-HT) pode estar envolvida no desenvolvimento do câncer colorretal, embora detalhes desse processo permaneçam desconhecidos. Camundongos knockout (KO) para triptofano hidroxilase 1 (Tph1) falham em sintetizar 5-HT e fornecem um sistema modelo apropriado para estudar o papel deste neuro-hormônio na carcinogênese colorretal. Animais Tph1KO apresentaram um desenvolvimento reduzido de tumores alográficos e tumores colorretais induzidos por colite. No entanto, o tratamento carcinogênico colorretal promoveu um aumento do número de tumores induzidos pela exposição à um carcinógeno. Também se observou uma alta intensidade de dano de DNA no nicho de células-tronco do cólon, bem como uma redução na populações de células enteroendócrinas e aumento daquelas unidades caliciformes. Antes da ativação da ataxia telangiectasia relacionada a Rad 3 (ATR) e proteína 53 relacionada à transformação (Trp53), a síntese de 5-HT promoveu a atividade da O-6-metilguanina-DNA metiltransferase (MGMT) em resposta à exposição carcinogênica. O resgata da síntese de 5-HT através do tratamento com 5-hidroxitriptofano reduziu o dano de DNA induzido pela radiação. O papel protetor da 5-HT foi confirmado em camundongos transgênicos com perda específica da expressão de Tph1 nos intestinos. Esta investigação demonstra um papel protetor da síntese de 5-HT contra o desenvolvimento da carcinogênese colorretal. / Serotonin (5-HT) activity may impact on the development of colorectal cancer. However, details of this process remain unknown. Tryptophan hydroxylase 1 knockout (Tph1KO) mice fail to synthesize 5-HT and provide an appropriate model system to study the role of this neurohormone in colorectal carcinogenesis. Tph1KO mice have a decreased development of allograft tumors and colitis-induced colorectal tumors. However, colorectal carcinogen treatment led to increased tumor numbers, with high DNA damage intensity in the colonic stem cell niche. It was related to decreased numbers of enteroendocrine cells but an increase in the goblet cell population. Indeed, 5-HT synthesis promoted O-6-methylguanine-DNA methyltransferase activity in response to azoxymethane before activating ataxia telangiectasia and Rad3 related (ATR) and transformation related protein 53 (Trp53) expression. Radiation-induced DNA damage could be rescued by 5-hydroxytryptophan. The protective role of 5-HT was confirmed in transgenic mice with intestine-specific loss of Tph1 expression. This investigation reveals a protective role of 5-HT synthesis against the development of colorectal carcinogenesis.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 128-159).

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Dissertation (Ph.D.)--University of Toledo, 2009. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Title from title page of PDF document. Bibliography: p. 174-180, p. 201-238.

Thesis (Ph.D.)--University of Alberta, 2009. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Department of Biochemistry. Title from pdf file main screen (viewed on August 11, 2009). Includes bibliographical references.

Thesis (Ph. D.)--Oregon State University, 2009. / Printout. Includes bibliographical references (leaves 101-112). Also available on the World Wide Web.

Theses (Ph. D.)--Marshall University, 2005. / Title from document title page. Includes abstract. Includes vitae. Document formatted into pages: contains xi, 149 p. Bibliography: p. 122-135.

The potential for environmental toxicants to cause genetic damage (genotoxicity) in organisms is a prominent concern because effects on DNA can compromise reproductive success and survival in organisms. Genotoxicity in male germ cells is of particular concern because damage to DNA in sperm may not be repaired and the consequences of damaged genetic material may be transgenerational (from parent to offspring). An integrated approach across multiple levels of biological organization is necessary to establish linkages between exposure to genotoxicants and subsequent effects at molecular and higher levels of biological organization. This thesis addresses the relation between toxicant-induced genotoxicity and reproductive success in zebrafish, and focuses on a model genotoxicant (hydrogen peroxide) and dissolved metals (radionuclide or non-radioactive forms) under controlled laboratory conditions. Uptake and depuration kinetics of a mixture of radionuclides (54Mn, 60Co, 65Zn, 75Se, 109Cd, 110mAg, 134Cs, and 241Am) were investigated, and radiation dose estimations were computed to link exposure and bioaccumulation with radiation dose. Cobalt (Co, non-radioactive) was selected as an environmentally relevant toxicant for investigation of genotoxicity and effects on reproductive success with a focus on male fish. Chronic exposure (12-d) to 0 – 25 mg l-1 Co resulted in reduced numbers of spawned eggs, lower fertilization success, and reduced survival of larvae to hatching. In male fish, DNA damage was detected in sperm and genes involved in DNA repair (xrcc5, xrcc6, and rad51) were induced in testes from some Co treatments, generally consistent with reduced reproductive success. No change in expression of repair genes in larvae spawned from parents exposed to Co was observed. Overall, results indicate that DNA damage and induction of DNA repair genes can occur rapidly after exposure to genotoxicants and that, if exposure levels are elevated, negative effects on reproduction can occur. Results are considered with particular focus on implications of male genotoxicity on reproductive success and the potential for transgenerational effects of toxicants.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 6 uppsatser.