title: Sex-dependent and non-monotonic enhancement and unmasking of methylmercury neurotoxicity by prenatal stress.
abstract: Methylmercury (MeHg) and prenatal stress (PS) are risk factors for neurotoxicity that may co-occur in human populations. Because they also share biological substrates and can produce common behavioral deficits, this study examined their joint effects on behavioral and neurochemical effects in male and female rats. Dams had access to 0, 0.5 or 2.5ppm MeHg chloride drinking water from two to three weeks prior to breeding through weaning. Half of the dams in each of these treatment groups also underwent PS on gestational days 16-17. This yielded 6 groups/gender: 0-NS, 0-PS, 0.5-NS, 0.5-PS, 2.5-NS, and 2.5-PS. Behavioral testing began in young adulthood and included fixed interval (FI) schedule-controlled behavior, novel object recognition (NOR) and locomotor activity, behaviors previously demonstrated to be sensitive to MeHg and/or mediated by brain mesocorticolimbic dopamine glutamate systems targeted by both MeHg and PS. Behavioral deficits were more pronounced in females and included impaired NOR recognition memory only under conditions of combined MeHg and PS, while non-monotonic reductions in FI response rates occurred, with greatest effects at the 0.5ppm concentration; the less reduced 2.5ppm FI response rates were further reduced under conditions of PS (2.5-PS). Correspondingly, many neurochemical changes produced by MeHg were only seen under conditions of PS, particularly in striatum in males and in hippocampus and nucleus accumbens in females, regions of significance to the mediation of FI and NOR performance. Collectively these findings demonstrate sex-dependent and non-monotonic effects of developmental MeHg exposure that can be unmasked or enhanced by PS, particularly for behavioral outcomes in females, but for both sexes in neurochemical changes, that were observed at MeHg exposure concentrations that did not influence either reproductive outcomes or maternal behavior. Thus, assessment of risks associated with MeHg may be underestimated in the absence of other extant risk factors with which it may share common substrates and effects.
authors: Department of Environmental Health Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States.
authors: Hiromi I
authors: HI
authors: Weston
authors: Department of Environmental Health Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States.
authors: Marissa E
authors: ME
authors: Sobolewski
authors: Department of Environmental Health Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States.
authors: Joshua L
authors: JL
authors: Allen
authors: Department of Environmental Health Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States.
authors: Doug
authors: D
authors: Weston
authors: Department of Environmental Health Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States.
authors: Katherine
authors: K
authors: Conrad
authors: Department of Environmental Health Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States.
authors: Sean
authors: S
authors: Pelkowski
authors: Department of Environmental Health Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States.
authors: Gene E
authors: GE
authors: Watson
authors: Department of Environmental Health Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States.
authors: Grazyna
authors: G
authors: Zareba
authors: Department of Environmental Health Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States. Electronic address: deborah_cory-slechta@urmc.rochester.edu.
authors: Deborah A
authors: DA
authors: Cory-Slechta
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D008297:Male; D008425:Maternal Behavior / Q000502:physiology / Q000523:psychology; D008767:Methylmercury Compounds / Q000378:metabolism / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D051381:Rats; D020318:Rats, Long-Evans; D021641:Recognition, Psychology / Q000187:drug effects; D012737:Sex Factors; D013315:Stress, Psychological / Q000150:complications*
chemical_list: D008767:Methylmercury Compounds; C004925:methylmercuric chloride; D003345:Corticosterone
keywords: Catecholamines; Corticosterone; Indoleamines; Methylmercury; Novel object recognition; Prenatal stress fixed interval schedule