title: Induction of the UDP-Glucuronosyltransferase 1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity.
abstract: Anticonvulsants can increase the risk of developing neurotoxicity in infants; however, the underlying mechanism has not been elucidated to date. Thyroxine [3,5,3',5'-l-tetraiodothyronine (T4)] plays crucial roles in the development of the central nervous system. In this study, we hypothesized that induction of UDP-glucuronosyltransferase 1A1 (UGT1A1)-an enzyme involved in the metabolism of T4-by anticonvulsants would reduce serum T4 levels and cause neurodevelopmental toxicity. Exposure of mice to phenytoin during both the prenatal and postnatal periods significantly induced UGT1A1 and decreased serum T4 levels on postnatal day 14. In the phenytoin-treated mice, the mRNA levels of synaptophysin and synapsin I in the hippocampus were lower than those in the control mice. The thickness of the external granule cell layer was greater in phenytoin-treated mice, indicating that induction of UGT1A1 during the perinatal period caused neurodevelopmental disorders. Exposure to phenytoin during only the postnatal period also caused these neurodevelopmental disorders. A T4 replacement attenuated the increase in thickness of the external granule cell layer, indicating that the reduced T4 was specifically associated with the phenytoin-induced neurodevelopmental disorder. In addition, these neurodevelopmental disorders were also found in the carbamazepine- and pregnenolone-16-α-carbonitrile-treated mice. Our study is the first to indicate that UGT1A1 can control neurodevelopment by regulating serum T4 levels.
authors.affiliation: Department of Pharmaceutics (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.).
authors.forename: Rika
authors.initials: R
authors.lastname: Hirashima
authors.affiliation: Department of Pharmaceutics (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.).
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Michimae
authors.affiliation: Department of Pharmaceutics (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.).
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takemoto
authors.affiliation: Department of Pharmaceutics (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.).
authors.forename: Aya
authors.initials: A
authors.lastname: Sasaki
authors.affiliation: Department of Pharmaceutics (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.).
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Pharmaceutics (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.).
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Department of Pharmaceutics (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.).
authors.forename: Robert H
authors.initials: RH
authors.lastname: Tukey
authors.affiliation: Department of Pharmaceutics (R.H., A.S., T.I., R.F.), Division of Biostatistics (H.M.), and Department of Pharmacognosy (H.T., Y.K.), School of Pharmacy, Kitasato University, Tokyo, Japan; and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.) fujiwarar@pharm.kitasato-u.ac.jp.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002220:Carbamazepine / Q000737:chemistry / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D050437:Genes, Developmental; D014453:Glucuronosyltransferase / Q000096:biosynthesis*; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008895:Milk, Human / Q000378:metabolism; D065886:Neurodevelopmental Disorders / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D010672:Phenytoin / Q000737:chemistry; D011247:Pregnancy; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D011297:Prenatal Exposure Delayed Effects / Q000097:blood / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D045442:Rotarod Performance Test; D013974:Thyroxine / Q000097:blood / Q000737:chemistry; D000099148:UGT1A1 Enzyme
chemical_list: D002220:Carbamazepine; D014453:Glucuronosyltransferase; D010672:Phenytoin; D011285:Pregnenolone Carbonitrile; D012333:RNA, Messenger; D013974:Thyroxine; D000099148:UGT1A1 Enzyme