title: Developmental exposure to fluoxetine modulates the serotonin system in hypothalamus.
abstract: The selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLU, Prozac®) is commonly prescribed for depression in pregnant women. This results in SSRI exposure of the developing fetus. However, there are knowledge gaps regarding the impact of SSRI exposure during development. Given the role of serotonin in brain development and its cross-talk with sex hormone function, we investigated effects of developmental exposure to pharmacologically relevant concentrations of FLU (3 and 30 nM (measured)) on brain neurotransmitter levels, gonadal differentiation, aromatase activity in brain and gonads, and the thyroid system, using the Xenopus tropicalis model. Tadpoles were chronically exposed (8 weeks) until metamorphosis. At metamorphosis brains were cryosectioned and levels of serotonin, dopamine, norepinephrine, and their metabolites 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were measured in discrete regions (telencephalon, hypothalamus and the reticular formation) of the cryosections using high-performance liquid chromatography. Exposure to 30 nM FLU increased the concentration of 5-hydroxyindoleacetic acid in hypothalamus compared with controls. FLU exposure did not affect survival, time to metamorphosis, thyroid histology, gonadal sex differentiation, or aromatase activity implying that the effect on the serotonergic neurotransmitter system in the hypothalamus region was specific. The FLU concentration that impacted the serotonin system is lower than the concentration measured in umbilical cord serum, suggesting that the serotonin system of the developing brain is highly sensitive to in utero exposure to FLU. To our knowledge this is the first study showing effects of developmental FLU exposure on brain neurochemistry. Given that SSRIs are present in the aquatic environment the current results warrant further investigation into the neurobehavioral effects of SSRIs in aquatic wildlife.
authors: Department of Environmental Toxicology, Uppsala University, Uppsala, Sweden. Cecilia.Berg@ebc.uu.se
authors: Cecilia
authors: C
authors: Berg
authors: Tobias
authors: T
authors: Backström
authors: Svante
authors: S
authors: Winberg
authors: Richard
authors: R
authors: Lindberg
authors: Ingvar
authors: I
authors: Brandt
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005473:Fluoxetine / Q000009:adverse effects*; D007031:Hypothalamus / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D007814:Larva / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D008675:Metamorphosis, Biological / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects*; D012733:Sex Differentiation / Q000187:drug effects; D012744:Sex Ratio; D013961:Thyroid Gland / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D013972:Thyrotropin / Q000378:metabolism; D060753:Water Quality; D014981:Xenopus
chemical_list: D001141:Aromatase; D005473:Fluoxetine; D018377:Neurotransmitter Agents; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013972:Thyrotropin
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