title: Selective cognitive deficits in adult rats after prenatal exposure to inhaled ethanol.
abstract: Increased use of ethanol blends in gasoline suggests a need to assess the potential public health risks of exposure to these fuels. Ethanol consumed during pregnancy is a teratogen. However, little is known about the potential developmental neurotoxicity of ethanol delivered by inhalation, the most likely route of exposure from gasoline-ethanol fuel blends. We evaluated the potential cognitive consequences of ethanol inhalation by exposing pregnant Long Evans rats to clean air or ethanol vapor from gestational days 9-20, a critical period of neuronal development. Concentrations of inhaled ethanol (5000, 10,000, or 21,000 ppm for 6.5h/day) produced modeled peak blood ethanol concentrations (BECs) in exposed dams of 2.3, 6.8, and 192 mg/dL, respectively. In offspring, no dose-related impairments were observed on spatial learning or working memory in the Morris water maze or in operant delayed match-to-position tests. Two measures showed significant effects in female offspring at all ethanol doses: 1) impaired cue learning after trace fear conditioning, and 2) an absence of bias for the correct quadrant after place training during a reference memory probe in the Morris water maze. In choice reaction time tests, male offspring (females were not tested) from the 5000 and 10,000 ppm groups showed a transient increase in decision times. Also, male offspring from the 21,000 ppm group made more anticipatory responses during a preparatory hold period, suggesting a deficit in response inhibition. The increase in anticipatory responding during the choice reaction time test shows that inhaled ethanol yielding a peak BEC of ~200mg/dL can produce lasting effects in the offspring. The lack of a dose-related decrement in the effects observed in females on cue learning and a reference memory probe may reflect confounding influences in the exposed offspring possibly related to maternal care or altered anxiety levels in females. The surprising lack of more pervasive cognitive deficits, as reported by others at BECs in the 200mg/dL range, may reflect route-dependent differences in the kinetics of ethanol. These data show that response inhibition was impaired in the offspring of pregnant rats that inhaled ethanol at concentrations at least 5 orders of magnitude higher than concentrations observed during normal automotive transport and fueling operations, which rarely exceed 100 ppb.
authors.affiliation: Toxicity Assessment Division, MD B105-04, MD B105-02, National Health Effects and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. Electronic address: oshiro.wendy@epa.gov.
authors.forename: W M
authors.initials: WM
authors.lastname: Oshiro
authors.affiliation: Toxicity Assessment Division, MD B105-04, MD B105-02, National Health Effects and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. Electronic address: beasley.tracey@epa.gov.
authors.forename: T E
authors.initials: TE
authors.lastname: Beasley
authors.affiliation: Toxicity Assessment Division, MD B105-04, MD B105-02, National Health Effects and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. Electronic address: mcdaniel.kathy@epa.gov.
authors.forename: K L
authors.initials: KL
authors.lastname: McDaniel
authors.affiliation: Toxicity Assessment Division, MD B105-04, MD B105-02, National Health Effects and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. Electronic address: taylor.michelemmt@gmail.com.
authors.forename: M M
authors.initials: MM
authors.lastname: Taylor
authors.affiliation: Environmental Public Health Division, MD B105-02, National Health Effects and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. Electronic address: evansky.paul@epa.gov.
authors.forename: P
authors.initials: P
authors.lastname: Evansky
authors.affiliation: Toxicity Assessment Division, MD B105-04, MD B105-02, National Health Effects and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. Electronic address: moser.ginger@epa.gov.
authors.forename: V C
authors.initials: VC
authors.lastname: Moser
authors.affiliation: Toxicity Assessment Division, MD B105-04, MD B105-02, National Health Effects and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. Electronic address: gilbert.mary@epa.gov.
authors.forename: M E
authors.initials: ME
authors.lastname: Gilbert
authors.affiliation: Toxicity Assessment Division, MD B105-04, MD B105-02, National Health Effects and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. Electronic address: bushnell.philip@epa.gov.
authors.forename: P J
authors.initials: PJ
authors.lastname: Bushnell
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002755:Choice Behavior / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced*; D003214:Conditioning, Classical / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D008297:Male; D018811:Maternal Exposure; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D020318:Rats, Long-Evans; D011930:Reaction Time / Q000187:drug effects; D065853:Spatial Learning / Q000187:drug effects
chemical_list: D000431:Ethanol
keywords: Biofuels; Cognitive function; Developmental; Ethanol; Inhalation; Prenatal exposure