title: Perinatal Administration of a Selective Serotonin Reuptake Inhibitor Induces Impairments in Reproductive Function and Follicular Dynamics in Female Rat Offspring.
abstract: BACKGROUND
  Up to 10% of pregnant women take antidepressants, of which selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed. Using a rodent model, we investigated the reproductive impacts of perinatal SSRI treatment on reproductive cyclicity and function in female offspring.
  
  
  METHODS
  Virgin Wistar rats were given oral vehicle (n = 10) or fluoxetine hydrochloride (FLX, 10 mg/kg/d; n = 11) from 2 weeks prior to mating until weaning. Pubertal onset and reproductive cyclicity in offspring were assessed. Blood and ovarian tissues were collected for measures of reproductive function.
  
  
  RESULTS
  Perinatal FLX tends to induce irregular reproductive cycles in adult offspring, which most commonly manifest as a prolonged estrus phase (FLX 34% vs control [CON] 10%) relative to CON offspring. The FLX offspring tended to have longer cycles (P = .052), had more secondary follicles (P = .0067), more total follicles (P = .0310), and increased apoptotic ovarian cells (P < .001). Prenatally exposed FLX offspring demonstrated elevated ovarian messenger RNA (mRNA) levels of ERβ (P = .008), Cry1 (P = .043), and tryptophan hydroxylase 2 (P = .024), independent of stage of cycle. Ovarian mRNA levels of brain and muscle Arnt-like protein 1 (P = .046) and Pet-1 (P = .021) were increased in FLX offspring a manner that was reproductive cycle stage dependent.
  
  
  CONCLUSIONS
  This is the first study to investigate the postnatal effects of maternal perinatal exposure to FLX on adult offspring reproduction. We show that genes that regulate serotonin signaling and action in the ovary are altered in prenatally FLX-exposed offspring, which when coupled with increased expression of components of the core Circadian Locomotor Output Cycles Kaput (CLOCK) gene regulatory loop may suggest an interaction between serotonergic signaling and clock gene signaling pathways leading to the altered reproductive phenotype.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Pediatrics McMaster University, Hamilton, Canada Department of Obstetrics and Gynaecology, Pediatrics McMaster University, Hamilton, Canada.
authors.forename: C J
authors.initials: CJ
authors.lastname: Moore
authors.affiliation: Department of Obstetrics and Gynaecology, Pediatrics McMaster University, Hamilton, Canada.
authors.forename: N E
authors.initials: NE
authors.lastname: DeLong
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Pediatrics McMaster University, Hamilton, Canada.
authors.forename: K A
authors.initials: KA
authors.lastname: Chan
authors.affiliation: Department of Obstetrics and Gynaecology, Pediatrics McMaster University, Hamilton, Canada.
authors.forename: A C
authors.initials: AC
authors.lastname: Holloway
authors.affiliation: Department of Obstetrics and Gynaecology, Pediatrics McMaster University, Hamilton, Canada Department of Biomedical Sciences, University of Guelph, Guelph, Canada.
authors.forename: J J
authors.initials: JJ
authors.lastname: Petrik
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Pediatrics McMaster University, Hamilton, Canada Department of Obstetrics and Gynaecology, Pediatrics McMaster University, Hamilton, Canada Department of Biomedical Sciences, University of Guelph, Guelph, Canada sloboda@mcmaster.ca.
authors.forename: D M
authors.initials: DM
authors.lastname: Sloboda
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D004971:Estrus / Q000187:drug effects; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage / Q000633:toxicity*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D018811:Maternal Exposure; D006080:Ovarian Follicle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D012098:Reproduction / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D014886:Weaning
chemical_list: D056926:CLOCK Proteins; D005473:Fluoxetine; D012333:RNA, Messenger; D017367:Selective Serotonin Reuptake Inhibitors
keywords: SSRI; clock genes; follicles; maternal depression; ovary; reproduction; serotonin