title: Depressive-like effect of prenatal exposure to DDT involves global DNA hypomethylation and impairment of GPER1/ESR1 protein levels but not ESR2 and AHR/ARNT signaling.
abstract: Several lines of evidence suggest that exposures to Endocrine Disrupting Chemicals (EDCs) such as pesticides increase the risks of neuropsychiatric disorders. Despite extended residual persistence of dichlorodiphenyltrichloroethane (DDT) in the environment, the mechanisms of perinatal actions of DDT that could account for adult-onset of depression are largely unknown. This study demonstrated the isomer-specific induction of depressive-like behavior and impairment of Htr1a/serotonin signaling in one-month-old mice that were prenatally exposed to DDT. The effects were reversed by the antidepressant citalopram as evidenced in the forced swimming (FST) and tail suspension (TST) tests in the male and female mice. Prenatally administered DDT accumulated in mouse brain as determined with gas chromatography and tandem mass spectrometry, led to global DNA hypomethylation, and altered the levels of methylated DNA in specific genes. The induction of depressive-like behavior and impairment of Htr1a/serotonin signaling were accompanied by p,p'-DDT-specific decrease in the levels of estrogen receptors i.e. ESR1 and/or GPER1 depending on sex. In contrast, o,p'-DDT did not induce depressive-like effects and exhibited quite distinct pattern of biochemical alterations that was related to aryl hydrocarbon receptor (AHR), its nuclear translocator ARNT, and ESR2. Exposure to o,p'-DDT increased AHR expression in male and female brains, and reduced expression levels of ARNT and ESR2 in the female brains. The evolution of p,p'-DDT-induced depressive-like behavior was preceded by attenuation of Htr1a and Gper1/GPER1 expression as observed in the 7-day-old mouse pups. Because p,p'-DDT caused sex- and age-independent attenuation of GPER1, we suggest that impairment of GPER1 signaling plays a key role in the propagation of DDT-induced depressive-like symptoms.
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna Street 12, 31-343 Krakow, Poland. Electronic address: kajta@if-pan.krakow.pl.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kajta
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna Street 12, 31-343 Krakow, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wnuk
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna Street 12, 31-343 Krakow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Rzemieniec
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna Street 12, 31-343 Krakow, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Litwa
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna Street 12, 31-343 Krakow, Poland.
authors.forename: Wladyslaw
authors.initials: W
authors.lastname: Lason
authors.affiliation: Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna Street 12, 31-343 Krakow, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zelek-Molik
authors.affiliation: Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna Street 12, 31-343 Krakow, Poland.
authors.forename: Irena
authors.initials: I
authors.lastname: Nalepa
authors.affiliation: Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna Street 12, 31-343 Krakow, Poland.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Rogóż
authors.affiliation: Department of Analytical Chemistry, Krakow University of Technology, Warszawska Street 24, 31-155 Krakow, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Grochowalski
authors.affiliation: Department of Animal Biotechnology, Faculty of Animal Sciences, University of Agriculture, Redzina Street 1B, 30-248 Krakow, Poland.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Wojtowicz
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015283:Citalopram / Q000627:therapeutic use; D003634:DDT / Q000737:chemistry / Q000633:toxicity*; D019175:DNA Methylation / Q000187:drug effects*; D003863:Depression / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D052244:Endocrine Disruptors / Q000737:chemistry / Q000633:toxicity*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D007536:Isomerism; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011897:Random Allocation; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018687:Antidepressive Agents, Second-Generation; D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha; C532507:GPER1 protein, mouse; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D015283:Citalopram; D003634:DDT
keywords: Aryl hydrocarbon receptor; Brain; DNA methylation; Depression; Estrogen receptors; Pesticide