別紙41 信果程博士(英文))Date of subn〕ission (n〕onth day, year)

Toshihiko EkiDepa11m引〕10f

Applied chemistry

StⅡdentlD NⅢηberD143440

and Life science
へPP11Canl's na11]e

09山 July 2021

KazunoriTakashima
SupeTvlsofs

Sachiko YOSI)idaTI〕on〕as Tion牙 1くWon琴 Soon

Abstract (Doctor)
Iitle ofThesis

A study on assessing syslemic inaammation due to malignanl ce11S and peslicide exposure

Approx. 80o words
InflanU11ation plays an imp01、tant l'ole in body defense mechanisn) as it fights off tl〕e invasion
Of foreign substances such as padlogens al'e tl'ying to coml)ron]ise oul' defense syS1引11. our body
UsuaHy l'esponse with lhe release of 桝'oinaammat01'y cytokines in ordel' to recl'uit ce11S such as
ma引'ophage and l'esident micl'oglia to eliminate the pathogens. Thel'e al'e two common {ypesinaammation 、¥hich al'e acute inaammation and chl'onic inaan〕malion. Acute ingamn〕ation is a l'apid
1、esponse fl'om lnitial msult to h〕itiate healil]g pl'ocess、、 1]ile C11ronic inflamnlalion usuaⅡy ocC山'Sacl'oss a longel'1〕eriod of time 、Nhen lhe body is undel' continuous and 御'010nged pel't1Ⅱ'bation' B0111
引'e equaⅡy dangerous as t11e progl'ession of inaan〕n]ation may lead lo systenlic inaamn〕alion.
Systen]ic inaammation is a l'esU110f cil'culating pl'oinaammatm'y cytokines W11icl〕 can cause multiple
1'eactions before disease ma】]ifestation. Theref01'e, it is hal'd to pinpoint the exact assault that causes
Systemic inaanlmation, makHlg it a prolninent t田'ge{ in multiple fields involving medicine, bi010gy、
Chen]istl'y and physi010gy.1his study pl'01)oses an assessment involving ce11Ular bi010gy, signal
PI'ocessing, rat study and genelic enginee"ng in m'del' 10 evaluate ule alta'ations coming fl'om
Systenuc lnnan〕matlon、

Chapt伽' 1 Consists of the gen引'al introduclion of this ulesis, explainino dle backσ1'ound、
motivations and objectives and dle stl'ucture of t11is d】esis.

Chapter 2 discusses on the evaluation of the ceⅡUlar dynamics throuoh malionant ce11S using
Scanning acoustic micl'oscope. Developlnent of non・i1ハasive obS引'valiona110olto assess dle changes
in ceⅡUlar levelis necessal'y as conventional appl'oaches foC11S m01'e on lissue and 田'gan. This study
focus on t11e dynamic ce11Ular changes during 111itotic phase as ceⅡ nucleU9 facililates nlost of t11e ce11
activities, making it a pl'ilne tal'get in disease study and drug design. MaHgnal]t ce11S wel'e 田'rested in
milotic phase by ce11 Cycle synchronization using demecolcine, a い'pical anlicancer drug mostly usedin chenlo‑1'adiot11el'apy.丁11e dynamic changes of lhe ce11 nucleus during mitotic phase、¥ere

SuccessfUⅡy capt11red using scanning acoustiC 111icl'OSC01)e and connTmed using confocal microscopy.
This result pl'ovided valuable insig11t hl unda'standing 111e a11el'ali01] of ceⅡ nucleus in l'eal tilne andaⅡ0、Ned us to explore t11e possibility to impl'ove dl'ug design and elucidate t11e disease mechanisln
This is an i111Portant advancement to brinfl scalu]ing acoustic microscope closel' to application inbiomedical neld.

Furthennore, tl〕is study expl01'ed the potential causes and effects of systelnic inaanlmation
thl'ough pesticide expostⅡ'e in rat study. Glyphosate, an active in即'edient of RounduP⑳,、¥ithgatl)ering conu'ovel'sies al'ound its usage 、Nas C110sen. Daily expoS山'e to suC11 Xenobiotjcs is proven to
be unsafe to hulnan as tl〕e continuous exposure nlight cause systemic hlaammation 、ヘノ1]ich is easy to
be overlooked、 Emel'gi11g evidences suggeS1 111at glyphosale is a potential hea11h l'isk and jeopal'dizeIhe envir011n〕ent, alus nlaking it a suHable {al'get to thggel' syslemic innamnlalion il〕 1'at study.
CI】apler 3 expl01'ed 、¥het11a' the tl'ansient innamnlation obsel'Yed in pl'evious chaplel' is systemic or
nol by looking at the gut・愉'ain axis. Gut・bl'ain axis is a bidil'ectiona11'elationshiP 11〕at affec{ each0111el'. one oftl)e feasible factors iS 1111'ougl】 1he metabolites pl'oduced by a〕e gut bacteria. The changes
01、1he σUt nlicl'obiola and metabolites al'e indicatiYe of innanlmation・n〕ediated alta'ation.1he result

SI】owed lhat thel'e is a stl'ong association in bet、veen the cel'ebe11al' developmental anonlalies anddis】'11Pted gut n〕icl'obiota and metabolites pl'oduction. These changes pointed to、¥ω'ds systenliciΠΠamn〕ation as dle maj01'桝'opagalor t11at might ful'ther il'ritate lhe symptoms.
C11aptel' 4 focus on the effects of prenatal expoS山'e on ale C引'ebe11ar deYelopnlent inOffspl'ing. PI'enatal exposul'e 、Nas C110sen because multiple bi010gical and physi010gical eYents
happened duhng pl'egnancy, making l)1'egnant dam more susceptible to altel'alions. The l'esult showedIhal altel'ation occun'ed in the offspl'ing C引'ebe11山n infel'ring t11al glyphosale mighl be developmental
ncul'otoxic, C11aptel' 5 descl'ibed ule altcl'ation of pro・innan}mal01'y cylokine l'ound in offsp"ng
Cel、ebe11Um. since 111e a11el'ation obsel、Yed in pl'evious C11aple】' n〕ig11t be nlediated by systelnic
inaamlnation, hence、 finding oul u〕e l)1'od11Clion of pl、oi】〕11anlmat01'y cylokines dul'ing eal'1ydevelopm引〕t is esseDlia1 10 lmdel'sland ule med〕anisnl behind 11〕e a11el"alion. TI〕e result S110圦ノed lhat
11'ansient inaammalion occun'ed in t11e cel'ebe11Unl ofjuV引lile male l'at although the l)1'oduction tinling
diffel'ed.

C11aptel' 6 expand t11e reseal'ch scope into adU11hood by examining ule social behavioralCI〕anges in nlatured animal. Animal behavior study is essenlialin understanding lhe bl、ain altel'ationand disease phenotype. The l'esult delnonSれ'aled that adult lnale l'ats b0Π1 介'om pl'enatal glyphosate
exposed da111 animals 、Nel'e less explorative, not groonling as lnuch and more anxious in social

hltel'action.1his implied cognitive h〕〕pairnlent, and hence, t11e l"esult infen'ed that the effects of1)1、enatal Gp exposul'e cal'ried on h〕to adulthood.
Taken together, scanning acoustic n]i口'oscope has the potentialto bl'idge cun'enl approaches
in ce11Ular study to tl'anslationa11'eseal'ch.11'acing d〕e livhlg ce11Ular dynamics change nlight l'eveal
m01'e on the aHel'ation caused by systenlic inaamlnation. prenatal glyphosale expoS山'e successfU11y
tri8gered systemic inaammation in the Fl male l'at even 、Nhen aley enlel'ed adulthood. T11e effects
圦ノere significant and assessable t11rough met110d010gy proposed in this study. This ilnplied tl〕at t11e

Proposed method010gy is tl'anslatable in hulnan study in 01'der to elucidate disease mechanism