Ci a ion: Ma in-Reina J, Dua e JA, Ce illos L, Bau is a JD, Mo eno I. Insec icide Rep oduc i e Toxici y P o ile: O ganophospha e, Ca bama e and
Py e h oids. J Toxins. 2017;4(1): 7
J Toxins
May 2017 Volume 4, Issue 1
© All igh s a e ese ed by Ma in-Reina J, e al.
Insec icide Rep oduc i e Toxici y
P o ile: O ganophospha e, Ca -
bama e and Py e h oids
In oduc ion
Pes icides a e de ined as “chemical subs ances used o p e en ,
des oy, epel o mi iga e any pes anging om insec s, oden s and
weeds o mic oo ganisms” [1]. The use o hese chemicals in mode n
ag icul u e has signi ican ly inc eased p oduc i i y. Bu i has also
signi ican ly inc eased he concen a ion o pes icides in ood and in
ou en i onmen , wi h associa ed nega i e e ec s on human heal h
[2]. Exposu e o pes icides is e y common wo ld-wide and is b oadly
known he acu e oxic e ec s o humans o pes icides ollowing a
high dose exposu e; howe e , knowledge abou ch onic low-dose
ad e se e ec s o speci ic pes icides is mo e limi ed [3]. Acu e and
delayed heal h e ec s, ange om simple i i a ion o he skin and
eyes o gene al malaise and ch onic and long e m se e e e ec s on
he ne ous sys em. Rep oduc i e unc ions can also be a ec ed,
wi h bi h de ec s, impai ed ecund abili y, in e ili y and al e ed
g ow h [4]. Cu en ly, only wo pes icides, a senical insec icides and
TCOD (a dioxin) ha e been designa ed by IARC as known human
ca cinogens, bu many o he s wi h wo ld-wide use a e suspec ed
human ca cinogens [1].
This pape will ocus on he dele e ious e ec s ha may appea
in he o sp ing, du ing ea ly and la e s ages o li e, a e p ena al
exposu e o insec icides, no only on women wi h di ec exposu e
bu also on subjec s wi h indi ec exposu e such as consume s o
esiden s o u al communi ies.
Me hodology
A sys ema ic li e a u e sea ch was unde aken o loca e and
e iew esea ch conce ning he p ena al e ec s o pes icides. The
e iew was designed o answe he ollowing ques ions:
Which a e he main oxic e ec s o he mos pes icides used
a ound he wo ld?
How pes icides can p oduce hese oxic e ec s? Which a e hei
modes o ac ion?
Sea ch s a egy
The Medline, Scopus and Web o knowledge ci a ion da abases
we e sea ched o ele an a icles published be ween 2000-2017
using combina ions o he ollowing e ms:
Full-leng h expe imen al a icles ela ed o pes icides and p ena al
oxic e ec s we e e ie ed. A o al numbe o 286 eco ds we e
ob ained when combina ions o all he keywo ds we e made, and
a e excluding he duplica es, he emaining a icles we e classi ied
acco ding he main ocus o each a icle. Abou li e a u e e iews,
a o al numbe o 390 ocused on o ganophospha es, ca bama es,
py e h oids and oxici y we e ound. The abs ac s o all a icles we e
ca e ully s udied, and he a icles epo ing he mode o ac ion and/
o p ena al oxic e ec s (animals and humans) o he di e en ypes
o pes icides we e included. A inal numbe o 53 s udies we e ound
ele an ha cons i u ed he main s uc u e o he p esen e iew.
Types o Pes icides
Pes icides can be classi ied by a ious c i e ia such as chemical
classes, unc ional g oups, mode o ac ion, and oxici y (Table 1) [5].
Some imes a e classi ied by he ype o a ge pes o which hey a e
applied. The ou majo classes a e hose o ungicides, he bicides,
Jose Ma in-Reina1, José A. Dua e1, Lucas
Ce illos2, Juan D. Bau is a3 and Isabel Mo eno1*
1A ea o Toxicology, Facul y o Pha macy, Uni e si y o Se illa,
Se illa, Spain
2A ea o Obs e ics, Vi gen del Rocío Uni e si a y Hospi al.
3Biochemis y Depa men , Facul y o Pha macy, Uni e si y o
Se illa
*Add ess o Co espondence
Isabel Mo eno, A ea o Toxicology, Facul y o Pha macy, Uni e si y
o Se illa, Se illa, Spain, Tel: +34 954 556762; Fax: +34 954 233765;
E-mail: imo [email protected]
Submission: 18 Ap il, 2017
Accep ed: 10 May, 2017
Published: 15 May, 2017
Copy igh : © 2017 Ma in-Reina J, e al. This is an open access a icle
dis ibu ed unde he C ea i e Commons A ibu ion License, which pe -
mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o-
ided he o iginal wo k is p ope ly ci ed.
Resea ch A icle
Open Access
Jou nal o
Toxins
Keywo ds: O ganophospha e; Ca bama e; Py e h oids; P ena al
exposu e; Toxic e ec s
Abs ac
Exposu e o pes icides is e y common wo ld-wide, and is b oadly
known he acu e oxic e ec s o humans o pes icides ollowing a high
dose exposu e; howe e , knowledge abou ch onic low-dose ad e se
e ec s o speci ic pes icides is mo e limi ed. Rep oduc i e unc ions
can be a ec ed, wi h bi h de ec s, impai ed ecund abili y, in e ili y
and al e ed g ow h. This pape will ocus on he dele e ious e ec s
ha may appea in he o sp ing, du ing ea ly and la e s ages o li e,
a e p ena al exposu e o insec icides, no only on women wi h di ec
exposu e bu also on subjec s wi h indi ec exposu e such as consume s
o esiden s o u al communi ies. P ena al exposu e o pes icides could
al e no mal e al de elopmen and could h ea en u u e wel a e. The
main changes obse ed in p ena al exposu e o o ganophospha es
a e al e a ions in he cen al ne ous sys em, in he me abolic and
ho monal sys em as endoc ine dis up o and o e he bi h ou comes.
Ca bama es may cause de elopmen al delay when he applica ions
o ca bama es du ing p egnancy we e nea by he home. Py e h oids
a e among he mos equen ly used pes icides and accoun o mo e
han one- hi d o he insec icides cu en ly ma ke ed in he wo ld. Fo
his eason he p ena al exposi ion used o be o long pe iods causing
clinical, biochemical and neu ological changes.
Pes icides O ganophospha es Ca bama es Py e h oids
P ena al
exposu e Toxic e ec s Newbo ns Mechanism
Ci a ion: Ma in-Reina J, Dua e JA, Ce illos L, Bau is a JD, Mo eno I. Insec icide Rep oduc i e Toxici y P o ile: O ganophospha e, Ca bama e and
Py e h oids. J Toxins. 2017;4(1): 7
J Toxins 4(1): 7 (2017) Page - 02
ISSN: 2328-1723
oden icides and insec icides [6]. Fu he mo e, wi hin each class,
se e al po en ially oxic subclasses exis , o example among
insec icides; one can ind o ganochlo ines, o ganophospho us
compounds, ca bama es, py e h oids, and many o he chemicals
(Table 2) [7].
Insec icides a e capable o killing insec s by pene a ing in o hei
bodies ia di ec con ac (de mal en y), o al, and/o espi a o y en y
[5]. Mos o he chemical insec icide in use oday a e neu o oxican s,
and ac by poisoning he ne ous sys em o he a ge o ganism
(Table 2) [8].
The O ganochlo ine Pes icides (OCPs) a e conside ed as
pe sis en o ganic pollu an s, once eleased in he en i onmen , hey
b eak down e y slowly in ai , wa e , soil and in li ing o ganisms.
As OCPs bio-magni y h ough he ood chain, consume s o ood
o animal o igin such as ish, mea , milk and dai y p oduc s end
up wi h high le els o exposu e and due o slow biodeg ada ion,
OCPs accumula e in he body [9]. Fo his eason, insec icides such
as o ganophospha es, py e h oids, and ca bama es ha e become
a ac i e al e na i es o OCPs because hey do no pe sis in he
en i onmen . O ganophospha e pes icides a e cu en ly he mos
hea ily used insec icide in US ag icul u e whe eas py e h oids a e
he mos common class o pes icide used in homes [10]. Howe e ,
ex ensi e use o hese p oduc s has culmina ed in cons an human
exposu e o pes icides ia domes ic use o he ood chain [11].
In his e iew, we will p o ide an o e iew o he oxic e ec s o
hese mos employed insec icides o e one o he mos sensible
popula ion, p egnan women and he newbo n. Fi s o all, we will
discuss mechanisms by which o ganophospha es, ca bama es, and
py e h oids may elici he oxic esponse a e he p ena al exposu e
and he po en ial consequences o his exposi ion.
Impac s o Insec icides on Rep oduc ion
O ganophospha es
O ganophospho us (OP) is he gene al name o o ganic
de i a i es o phospho us. They a e he mos commonly used
insec icides in he wo ld because hei uns able chemical s uc u e
leads o apid hyd olysis and li le long- e m accumula ion in he
a) Based on oxici y c i e ia.
Type Toxici y le el LD50 o he a (mg/kg body weigh )
O al De mal
Ia Ex emely
haza dous < 5 < 50
Ib Highly haza dous May-50 50-200
II Mode a ely
haza dous 50-2000 200-2000
UUnlikely 5000 o
highe
b) Based on a ge pes
Type Pes
Algicide Algae
A icide Bi ds
Bac e icide Bac e ia
Fungicide Fungi
He bicide Weeds
Insec icide Insec s
Mi icide Mi es
Molluscide Snails, slugs
Nema icide Nema odes
Piscide Fish
Roden icide Roden s
(c) Based on he mode o o mula ion
Physical s a e Cha ac e is ics
Emulsi iable
concen a es
Do no equi e cons an agi a ion p io o each
applica ion
We able powde s Requi e cons an agi a ion p io o each applica ion
G anules Ob ained by mixing he ac i e ing edien wi h clay
Bai s Ob ained by mixing he ac i e ing edien wi h ood
Dus s Dus s canno be mixed wi h wa e and hey mus be
applied d y
Table 1: Classi ica ion o pes icides [5].
Table 2: Insec icide classi ica ion. IRAC MoA classi ica ion e sion 8.1, Ap il
2016.
Main G oup and P ima y Si e o Ac ion
Chemical Sub-g oup
o exempli ying Ac i e
Ing edien
1 Ace ylcholines e ase (AChE) inhibi o s
Ne e ac ion
1A
Ca bama es
1B
O ganophospha es
2 GABA-ga ed chlo ide channel blocke s
Ne e ac ion
2A
Cyclodiene O ganochlo ines
2B
Phenylpy azoles (Fip oles)
3 Sodium channel modula o s
Ne e ac ion
3A
Py e h oids, Py e h ins
3B
DDT, Me hoxychlo
4 Nico inic ace ylcholine ecep o (nAChR)
compe i i e modula o s
Ne e ac ion
4A
Neonico inoids
4B
Nico ine
4C
Sul oximines
4D
Bu enolides
4E
Mesoionics
5 Nico inic ace ylcholine ecep o (nAChR)
allos e ic modula o s
Ne e ac ion
Spinosyns
6 Glu ama e-ga ed chlo ide channel (GluCl)
allos e ic modula o s
Ne e and muscle ac ion
A e mec ins, Milbemycins
9 Cho do onal o gan TRPV channel
modula o s
Ne e ac ion
Py idine azome hine
de i a i es
14 Nico inic ace ylcholine ecep o (nAChR)
channel blocke s
Ne e ac ion
Ne eis oxin analogues
19 Oc opamine ecep o agonis s
Ne e ac ion Ami az
22 Vol age-dependen sodium channel
blocke s
Ne e ac ion
22A
Oxadiazines
22B
Semica bazones
28 Ryanodine ecep o modula o s
Ne e and muscle ac ion Diamides
29 Cho do onal o gan Modula o s - unde ined
a ge si e
Ne e ac ion
Flonicamid
Ci a ion: Ma in-Reina J, Dua e JA, Ce illos L, Bau is a JD, Mo eno I. Insec icide Rep oduc i e Toxici y P o ile: O ganophospha e, Ca bama e and
Py e h oids. J Toxins. 2017;4(1): 7
J Toxins 4(1): 7 (2017) Page - 03
ISSN: 2328-1723
en i onmen [12].
Toxici y mechanism
a) Inhibi ion o ace ylcholines e ase (AChE)
The well known OP acu e oxici y is ini ia ed by inhibi ion o
ace ylcholines e ase (AChE). This enzyme is classed as a B es e ase
whose majo ole is he hyd olysis o ace ylcholine (ACh). ACh
is a majo neu o ansmi e in he pe iphe al and cen al ne e
sys em. This inhibi ion dis up s he abili y o he enzyme o bind o
i s no mal subs a e wi h he subsequen accumula ion o ACh a
ne e endings [13,14]. Consequen ly, an o e s imula ion ollowed
by desensi iza ion o musca inic and nico inic ACh ecep o s occu s.
Inhibi ion o AChE occu s a e phospho yla ion o hyd oxyl g oup
a se ine a he ac i e si e o he enzyme. Depending on he deg ee o
AChE inhibi ion, choline gic s imula ion may lead o hype ac i i y o
exci able issues, causing ascicula ion, seizu es, con ulsions, se e e
muscle pa alysis, hype sec e ion om sec e o y glands, espi a o y
ailu e, coma, and dea h [15,16].
Based on sys ema ic in es iga ions o he ela ionship be ween
chemical s uc u e and inhibi ion o AChE, i is appa en ha he
single mos impo an p ope y equi ed in an o ganophospha e o
an icholines e ase ac i i y is chemical eac i i y. S uc u e-ac i i y
s udies ha e e ealed a di ec ela ionship be ween an icholines e ase
ac i i y and eac i i y o he phospho us a om [17]. Thus he mos
impo an p ope ies equi ed o an icholines e ase ac i i y a e (1)
he s e ic p ope ies o di use in o he ac i e si e go ge and o m a
s able enzyme-inhibi o complex and (2) su icien eac i i y o he
eac ion cen e , phospho us, o accep a nucleophilic a ack om he
se ine hyd oxyl in he ac i e si e [18].
Aside om he inhibi ion o AChE, ce ain OPs can cause
ano he ype o oxici y called O ganophospha e Induced Delayed
Polyneu opa hy (OPIDP). I is cha ac e ized by degene a ion o long
axons in he cen al and pe iphe al ne ous sys em and consequen
a axia and pa alysis ha appea abou 2-3 weeks a e exposu e o
la e [19]. OPIDP is ini ia ed by phospho yla ion and subsequen
aging o >70% o he unc ional Neu opa hy Ta ge Es e ase (NTE).
NTE may ha e impo an unc ions du ing b ain de elopmen
h ough in ol emen in cell-signaling pa hways be ween neu ons
and glial cells [16].
b) Oxida i e s ess and apop osis
As i has been said abo e, he main a ge o ac ion o OP is he
inhibi ion o AChE; bu i has also pos ula ed ha bo h acu e and
ch onic exposu es o hese compounds al e he edox p ocesses and
hus induce oxida i e s ess [20].
Pes icides a e known o dis u b oxida i e homeos asis
h ough di ec o indi ec pa hways, including mi ochond ial o
ex ami ochond ial p oduc ion o ee adicals, hiol oxida ion, and
deple ion o cellula an ioxidan ese oi s [21]. Pes icide damage
is gene a ed by he imbalance be ween Reac i e Oxygen Species
(ROS) p oduc ion and elimina ion [22]. ROS may be p oduced as he
esul o he me abolism o o ganophospha es by cy och ome P450s
by addi ion o one a om o molecula oxygen in o he molecule by
an elec on anspo pa hway. The OP change no mal an ioxidan
homeos asis esul ing in an ioxidan deple ion [23].
Addi ionally, dis up ing e ec s o o ganophospha es on glucose
homeos asis ha e been epo edly linked o oxida i e [21]. Glucose is
he sou ce o educing equi alen s (NADH, NADPH, and GSH e c.)
which a e in ol ed in he ecycling o oxidized cellula an ioxidan s.
On he o he hand, hype glycemia inc eases non-enzyma ic glyca ion
leading o he o ma ion o ad anced glyca ion end p oduc s (AGEs),
which al e s uc u e and unc ions o p o eins, which ac i a e speci ic
memb ane ecep o s called ecep o s o ad anced glyca ion end
p oduc s (RAGE) and induce an in acellula oxida i e s ess. When
ROS le els exceed he sca enging capaci y o he body, mi ochond ia
will swell wi h pe meabili y changes. I has been epo ed ha
exposu e o OPs causes mi ochond ial damages and he cy och ome
c is eleased in o he cy oplasm, and he caspase cascade is ac i a ed,
which lead o apop osis [22].
c) Endoc ine dis up o s
Mos endoc ine dis up ing pes icides mimic es ogen unc ion
by ac ing as a ligand o ecep o , con e ing o he s e oids o ac i e
es ogen o inc easing he exp ession o es ogen esponsi e genes as
shown by some o ganochlo ines, o ganophospha es, ca bama es, and
py e h oids [21]. These pes icides can a ec he endoc ine sys em in
any s age o ho monal egula ion, om syn hesis o ho mone ecep o
binding, esul ing in ep oduc i e and de elopmen al ad e se e ec s
[24,25]. Thus, esul s epo ed by Walsh e al. showed ha dime hoa e
inhibi ed s e oidogenesis in bo h a dose- and ime-dependen manne
by blocking ansc ip ion o he S e oidogenic Acu e Regula o y
(S AR) gene [26]. O he OPs a e capable o in e e ing wi h he
endoc ine unc ion by inhibi ing he binding o hy oid ho mones
o hei co esponding ecep o s. OPs such as chlo py i os a e also
able o inhibi ad enal s e oidogenesis, hus a ec ing he ho monal
s a us [21,24].
P ena al exposu e and i s consequences o he new bo n
In u e o exposu e is he i s poin o con ac wi h en i onmen al
xenobio ics ha may a ec he ma e nal-placen al- e al balance [27].
This is belie ed o be he c i ical exposu e pe iod o OP insec ides
o human neu ological de elopmen and is, by de ini ion, he only
ele an exposu e pe iod o bi h ou comes [28].
a) E ec s in he cen al ne ous sys em
P ena al exposu e causes dis up ion in b ain de elopmen , leading
o beha io al de ici s, impai ed cogni i e and mo o unc ions, and
al e a ions in he choline gic sys em ha a ec s lea ning and memo y
p ocesses [29]. Thus, Young e al. assess he ela ionship be ween in
u e o and ea ly pos na al OP exposu e and neona al neu obeha io
in humans, as measu ed by se en clus e s (habi ua ion, o ien a ion,
mo o pe o mance, ange o s a e, egula ion o s a e, au onomic
s abili y, and e lex) on he B azel on Neona al Beha io al Assessmen
Scale (BNBAS) [30]. Exposu e o OP pes icides was de e mined by
u ina y le els o Dialkylphospha e (DAP) me aboli es, including
dime hyl and die hylphospha e me aboli es. The ela ionship be ween
exposu e and BNBAS pe o mance was examined by he median
age a assessmen , 3 days. Resul s a e sugges i e o a de imen al
impac o in u e o OP exposu e, as measu ed by o al DAP, on e lex
unc ioning, pa icula ly in hose in an s assessed a e 3 days o li e.
Speci ically, he mos common p imi i e e lexes a ed as abno mal
Ci a ion: Ma in-Reina J, Dua e JA, Ce illos L, Bau is a JD, Mo eno I. Insec icide Rep oduc i e Toxici y P o ile: O ganophospha e, Ca bama e and
Py e h oids. J Toxins. 2017;4(1): 7
J Toxins 4(1): 7 (2017) Page - 04
ISSN: 2328-1723
included: oo ing (23%), passi e esis ance-legs (39%), walking
(25%), incu a ion (40%), and Mo o e lex (18%).
b) Me abolic and ho monal al e a ions
Pes icides can cause endoc ine dis up ion, ei he by di ec
in e ac ion wi h ecep o s o al e a ion o he enzymes in ol ed in
s e oid ho mone syn hesis and me abolism. They can po en ially al e
ho mone concen a ions in blood and issues [27]. Thus, Usmani e
al. obse ed ha OP pes icides we e e y po en inhibi o s o he
p oduc ion o he p ima y me aboli es o CYP3A4 and inhibi ed
majo es os e one me aboli es noncompe i i ely and i e e sibly
[31]. Fu he mo e, OP componen s a e o a ec he male ep oduc i e
sys em by such mechanisms as educ ion o spe m ac i i ies,
inhibi ion o spe ma ogenesis, educ ion o es is weigh s, damaging
spe m DNA, and inc easing abno mal spe m mo phology [5]. An
inc eased le el o FSH accompanying a dec eased le el o inhibin B,
es os e one, LH, and F ee And ogen Index (FAI) in associa ion wi h
exposu e o some OP insec icides [21].
c) E ec s o e he bi h ou comes
I has been p o ed he associa ion be ween OP exposu e
and bi h ou comes, sugges ing a dec ease in bi h weigh and
head ci cum e ence in newbo ns bo n om mo he s wi h low
PON1 ac i i y ha we e exposed o OP pes icides [32]. Also has
been obse ed a ai ly consis en ad e se associa ion o in u e o
o ganophospha e pes icide exposu e wi h ges a ional du a ion.
These associa ions wi h ges a ional age may be biologically plausible
gi en ha o ganophospha e pes icides dep ess cholines e ase and
ace ylcholine s imula es con ac ion o he u e us [33].
Ca bama es
Toxici y mechanism
The inhibi ion o AChE by a ca bama e insec icide occu s by
a mechanism i ually iden ical o ha desc ibed ea lie o an
o ganophospho us es e [17]. As wi h o ganophospha es, he signs
and symp oms a e based on excessi e choline gic s imula ion.
Unlike o ganophospha e poisoning, ca bama e poisonings end
o be o sho e du a ion because he inhibi ion o ne ous issue
ace ylcholines e ase is e e sible, and ca bama es a e mo e apidly
me abolized [34].
P ena al exposu e and i s consequences o he new bo n
The s udy o he ca bama e exposu e in p egnan women is
usually made in associa ion wi h o he pes icides mo e used as
o ganophospha es and py e h oids. And he esul s ob ained
a e o en due o hese las mo e han o he ca bama es. Thus, he
ca bama e exposu e o he p egnan women was s udied by Fo de e
al. [35]. The e alua ion o his exposi ion was made by looking o
he p esence o wo ca bama e me aboli es (p opoxu me aboli e,
2-Isop opoxyphenol (2-IPP) and ca bo u anphenol). Resul s showed
e y low o no exis en le el o hese me aboli es h oughou he
en Ca ibbean coun ies sampled in his s udy. On he o he hand,
Ca michael e al. s udied he ela ionship be ween esiden ial
ag icul u al pes icide exposu es (including ca bama es) and isks o
selec ed bi h de ec s among o sp ing [36]. Resul s o his s udy did no
indica e s ong associa ions o he s udied bi h de ec s wi h esiden ial
p oximi y o ag icul u al pes icide applica ions, e en hough isk o
bi h de ec s wi hin an a ea o high pes icide use was in es iga ed. In
a p e ious s udy, Sheldon e al. ied o ela e neu ode elopmen al
diso de s and p ena al esiden ial p oximi y o ag icul u al pes icides
(o ganophopha es, o ganochlo ines, py e h oids, and ca bama es)
[37]. The main ela ionships we e de ec ed be ween o ganophopha es,
o ganochlo ines, and py e h oids. Only when he applica ions o
ca bama es du ing p egnancy we e nea by he home i was sugges ed
an associa ion be ween hese pes icides and de elopmen al delay.
In spi e o he lack o esul s abou he ep oduc i e oxici y o
ca bama es in human, he e a e au ho s ha ha e s udied he main
oxic e ec s in o sp ings when p egnan a s we e exposed o he
mos used ca bama es pes icides. Thus, Mish a e al. s udied he e ec s
o ca bo u an, a ca bama e pes icide, in a o sp ing, a e a ch onic
ges a ional exposu e [38]. Resul s showed a dec eased neu ogenesis,
al e ed neu onal and glial di e en ia ion, inc eased cell dea h in
he hippocampus, and cogni i e impai men s in a o sp ing. The
obse ed dec ease in neu ogenesis in he p esen s udy can be a
esul o educ ion in he p oli e a ion a e, dec eased su i al and
ma u a ion o newbo n neu ons, al e ed cellula a e speci ica ion,
o a combina ion o all h ee e ec s. A la e s udy wi h ca bosul an
showed ha his ca bama e also a ec he neu ogenesis and synap ic
de elopmen in a o sp ing a e exposu e du ing he emb yonic
pe iod. A dose dependen educ ion in body weigh was obse ed in
pups exposed o ca bosul an. Also showed a dec ease in hei su ace
igh ing e lex compa ed wi h he con ol. In he nega i e geo axis
pa adigm, con ol animals u ned he 45° slope apidly. Howe e ,
pups exhibi ed a s a is ically signi ican delay in e-o ien a ion on
exposu e o inc easing doses o ca bosul an. Mo eo e , le els o
MDA and p o ein ca bonyl we e ele a ed in he ca bosul an exposed
pups compa ed wi h he con ol and while exposu e o his ca bama e
dose dependen ly p oduced a decline in he le els o AChE [39].
Py e h oids
Owing o hei ela i ely low oxici y o mammals in con as o
o ganophospho us insec icides, syn he ic py e h oids a e among he
mos equen ly used pes icides and accoun o mo e han one- hi d
o he insec icides cu en ly ma ke ed in he wo ld [40]. The i s
py e h oid pes icide, alle h in, was iden i ied in 1949. I s s uc u e
and hose o o he py e h oids wi h he basic cyclop opane ca boxylic
es e s uc u e we e called ype I py e h oids. The insec icidal ac i i y
o syn he ic py e h oids was enhanced u he by he addi ion o a
cyano g oup a he benzylic ca bon a om o gi e α-cyano ( ype II)
py e h oids such as cypheno h in and cype me h in [41].
The epo ed oxic e ec s o py e h oids include neu o oxici y,
skin con ac oxici y, espi a o y oxici y and ep oduc i e sys em
oxici y [40]. Type I py e h oids e ec s ypically include apid onse
o agg essi e beha io and inc eased sensi i i y o ex e nal s imuli,
ollowed by ine emo , p os a ion wi h coa se whole body emo ,
ele a ed body empe a u e, coma, and dea h. The e m T-synd ome
( om emo ) has been applied o Type I esponses. Type II e ec s a e
usually cha ac e ized by pawing and bu owing beha io , ollowed
by p o use sali a ion, inc eased s a le esponse, abno mal hindlimb
mo emen s, and coa se whole body emo s ha p og ess o sinuous
w i hing (cho eoa he osis). Clonic seizu es may be obse ed p io o
Ci a ion: Ma in-Reina J, Dua e JA, Ce illos L, Bau is a JD, Mo eno I. Insec icide Rep oduc i e Toxici y P o ile: O ganophospha e, Ca bama e and
Py e h oids. J Toxins. 2017;4(1): 7
J Toxins 4(1): 7 (2017) Page - 05
ISSN: 2328-1723
dea h. Body empe a u e usually is no inc eased, bu may dec ease.
The e m CS-synd ome ( om cho eoa he osis and sali a ion) has
been applied o Type II esponses [42].
Mechanisms o ac ion
a) E ec s on sodium channels
The mechanisms by which py e h oids alone a e oxic a e
complex and become mo e complica ed when hey a e co o mula ed
wi h pipe onyl bu oxide, an o ganophospho us insec icide, o bo h,
as hese compounds inhibi py e h oid me abolism.
The main e ec s o py e h oids a e on sodium and chlo ide
channels. As a esul , exci able (ne e and muscle) cells a e he
p incipal a ge s o py e h oid oxici y, which is mani es as
diso de ed unc ion a he han s uc u al damage [41]. Py e h oids
slowed Vol age-Ga ed Sodium Channels (VGSC) ac i a ion leading
o a dec ease in peak Na+ cu en . Py e h oids slowed VGSC
inac i a ion and deac i a ion leading o a p olonged VGSC open
ime. Type II py e h oids p olonged channel open ime mo e han
ype I py e h oids. The longe channel open ime esul s in mo e Na+
en e ing he cell leading o hype exci abili y wi h ype I py e h oids,
memb ane depola iza ion and conduc ion block wi h ype II
py e h oids. E en hough no e e y VGSC is al e ed by py e h oids,
modi ica ion o a small pe cen age o VGSCs can inc ease Na+
cu en subs an ially [43,44]. This is so-called sodium ‘ ail cu en ’. I
a sodium ail cu en is su icien o hold he cell memb ane po en ial
abo e h eshold, an abno mally ea ly second ac ion po en ial will
occu and a epe i i e s ain o ac ion po en ials can be igge ed. This
is he likely mechanism unde lying py e h oid- induced pa aes hesiae.
Despi e he p esence o ail cu en s, cells may con inue o unc ion,
albei a an abno mally high le el o exci a ion. Howe e , he e may
come a poin when hey canno sus ain unc ion a his le el and
wha has been e med ‘conduc ion block’ esul s. Conduc ion block
may be induced by exposu e o high concen a ions o ei he ype II
py e h oids (when he sodium cannel is kep open unduly long) o
ype I py e h oids (when a la ge ampli ude ail cu en is p oduced)
[41].
Thus, i can be said ha o he Type I and Type II s uc u al
subclasses o py e h oids, quali a i e di e ences in sodium channel
modi ica ion a e gene ally co ela ed wi h he p oduc ion o di e en
in oxica ion synd omes, sugges ing ha ac ions on sodium channels
a e su icien o accoun o he acu e oxici y o his insec icide class
[45].
b) E ec s on chlo ide channel
One addi ional a ge o ype II py e h oids is he memb ane
chlo ide ion cannel. The ol age-ga ed chlo ide channel was hen
p oposed as a a ge and o del ame h in a leas , his does appea
o be su icien ly sensi i e. Indeed i is possible o an agonize
bo h he sali a ion and cho eoa he osis, which a e he p ominen
cha ac e is ics o ype II py e h oid poisoning, wi h chlo ide channel
agonis s [46]. A ela i ely high concen a ions, py e h oids can also
ac on GABA-ga ed chlo ide channels, which may con ibu e o he
seizu es seen in se e e ype II poisoning [41].
c) Endoc ine dis up o
In spi e o se e al epidemiological s udies ha e linked
en i onmen al exposu e o py e h oids o al e a ions o he
ep oduc i e heal h o adul male subjec s, Saillen ai e al. showed
in a sys ema ic e iew ha se e al in i o sc een s udies sugges ha
ce ain py e h oids may ha e he po en ial o a ec he es ogenic
and and ogenic pa hways, bu a ailable da a do no p o ide e idence
o s ong in e ac ions. I has been p oposed ha he biphenyl
e he moie ies sha ed by se e al py e h oids (e.g. cype me h in,
del ame h in, es en ale a e, pe me h in) may play a ole in hei
in e ac ion wi h he ho mone ecep o s [47].
P ena al exposu e and i s consequences o he new bo n
New bo n babies and child en a e o en exposed o py e h oids
o long pe iods by he use o liquid apo ize s. Occupa ional and
expe imen al s udies indica e ha py e h oids can cause clinical,
biochemical and neu ological changes, and ha exposu e o
py e h oids du ing o ganogenesis and ea ly de elopmen al pe iod is
especially ha m ul [48].
a) E ec s in he cen al ne ous sys em
The e ec o exposu e o a pups du ing ea ly de elopmen al
s ages o py e h oids on Blood-B ain Ba ie (BBB) pe meabili y was
in es iga ed by Sinha e al. [48]. Resul s indica ed, ha inhala ion
o py e h oids du ing ea ly li e may lead o ad e se e ec on in an s
causing signi ican abno mali ies a ec ing he CNS by b eaching he
BBB. The damage was mo e du ing pos na al and pe ina al exposu es
han du ing he p ena al exposu e. In he la e case, he blood-
placen al ba ie is o med/de eloped which limi s he a ailabili y o
he py e h oid. A la e s udy, showed he e ec s o p ena al exposu e
o pe me h in on he de elopmen o ce eb al a e ies in e al b ains,
neu o ansmi e in neona al b ains, and locomo o ac i i ies in
o sp ing mice. This exposi ion in u e o caused e al b ain ascula
mal o ma ions and changes in mo o beha io in adul mice [49].
b) Epidemiological s udies
Se e al epidemiologic s udies ha e been pe o med. Thus, Qi
e al. showed ha p ena al exposu e o ele a ed le els o py e h oid
pes icides was associa ed wi h educed neu ode elopmen o in an s
om somewhe e o Jiangsu P o ince (China) [50]. O he au ho s
ha e been measu ed py e h oid me aboli es in biological samples,
hus, Dewailly e al. demons a ed an ex ensi e use o py e h oid
compounds such as pe me h in and cype me h in in Ca ibbean
households measu ing i s me aboli es concen a ions in Ca ibbean
p egnan women u ine [51]. Be on e al. analyzed 171 meconium
samples collec ed in he Pica die egion o no he n F ance looking
o pes icides and i s me aboli es [52]. The py e h oids cype me h in
and cy lu h in we e de ec ed in only 11 and 3 samples, espec i ely,
bu we e p esen a high concen a ions han he o he s udied
pes icides. The high concen a ions obse ed in some samples may
sugges di ec exposu e o he mo he h ough use a home o in he
wo kplace.
P ena al exposu e o py e h oid insec icides and bi h ou comes
we e s udied in Ru al No he n China by Ding e al. [53]. No
associa ions we e ound be ween indi idual o o al me aboli e
le els and bi h leng h, head ci cum e ence, o ges a ional du a ion,
howe e , an ad e se associa ion o p ena al exposu e o py e h oids

Ci a ion: Ma in-Reina J, Dua e JA, Ce illos L, Bau is a JD, Mo eno I. Insec icide Rep oduc i e Toxici y P o ile: O ganophospha e, Ca bama e and
Py e h oids. J Toxins. 2017;4(1): 7
J Toxins 4(1): 7 (2017) Page - 06
ISSN: 2328-1723
as measu ed by u ina y me aboli es wi h bi h weigh was epo ed.
On he o he hand, associa ions o bi h de ec s wi h esiden ial
p oximi y o comme cial ag icul u al pes icide applica ions in
Cali o nia we e made. Mos o he indi idual pes icides we e no
associa ed wi h inc eased isk. Py e h oids only we e associa ed wi h
c aniosynos osis, bu his esul should be in e p e ed wi h cau ion
gi en he no el y o his in es iga ion and po en ial alse posi i e due
o mul iple es ing [36].
Conclusion
In summa y, o ganophospha es, ca bama es and py e h oids
a e less pe sis en in na u e han o ganochlo ine pes icides bu e en
hough hey a e no sa e o humans exposed o small concen a ions
bu along hei li e. Nowadays he e is a g owing end o educing
he use o o ganophospha es pes icides and eplaced by ca bama es
and py e h oids, due i s oxic e ec s. The main ou e o exposu e is
h ough die bu his exposi ion inc ease when people a e li ing in
u al a eas nea o cul u es. P egnan women a e isk popula ion and
i has been p o ed he oxic e ec s o o ganophospha es, ca bama es
and py e h oids in o sp ings. Thus, o ganophospha es, causes
dis up ion in b ain de elopmen , leading o beha io al de ici s,
impai ed cogni i e and mo o unc ions, and al e a ions in he
choline gic sys em ha a ec s lea ning and memo y p ocesses. The
ca bama e exposu e in p egnan women is usually made in associa ion
wi h o he pes icides. The e is a lack o esul s abou he ep oduc i e
oxici y o ca bama es in human. The epidemiological s udies made
only associa e ad e se e ec s in o sp ing when he applica ions o
ca bama es du ing p egnancy we e nea by he home. New bo n
babies and child en a e o en exposed o py e h oids o long pe iods
by he use o liquid apo ize s a home. This exposi ion can cause
clinical, biochemical and neu ological changes, being especially
ha m ul i ha exposu e o py e h oids is du ing o ganogenesis and
ea ly de elopmen al pe iod.
Re e ences
1. Ala anja MCR (2009) Pes icides Use and Exposu e Ex ensi e Wo ldwide.
Re En i on Heal h 24: 303-309.
2. Tago D, Ande sson H, T eich N (2014) Pes icides and heal h: A e iew o
e idence on heal h e ec s, alua ion o isks, and bene i -cos analysis. Ad
Heal h Econ Heal h Se Res 24: 203-295.
3. Ala anja MC, Bonne MR (2012) Occupa ional pes icide exposu es and
cance isk: a e iew. J Toxicol En i on Heal h B C i Re 15: 238-263.
4. Collo a M, Be azzi PA, Bolla i V (2013) Epigene ics and pes icides.
Toxicology 307: 35-41.
5. Kim KH, Kabi E, Jahan SA (2017) Exposu e o pes icides and he associa ed
human heal h e ec s. Sci To al En i on 575: 525-535.
6. Ak a MW, Sengup a D, Chowdhu y A (2009) Impac o pes icides use in
ag icul u e: hei bene i s and haza ds. In e discip Toxicol 2: 1-12.
7. Hols ege CP, Bae AB (2004) Insec icides. Cu T ea Op ions Neu ol 6:17-
23.
8. Casida JE (2009) Pes oxicology: he p ima y mechanisms o pes icide
ac ions. Chem Res Toxicol 22: 609-619.
9. M ema EJ, Rubino FM, B ambilla G, Mo e o A, Tsa sakis AM, e al. (2013)
Pe sis en o ganochlo ina ed pes icides and mechanisms o hei oxici y.
Toxicology 307: 74-88.
10. Rosas LG, Eskenazi B (2008) Pes icides and child neu ode elopmen . Cu
Opin Pedia 20:191-197.
11. Pe ei a LC, de Souza AO, F anco Be na des MF, Pazin M, Tasso MJ, e
al. (2015) A pe spec i e on he po en ial isks o eme ging con aminan s
o human and en i onmen al heal h. En i on Sci Pollu Res In 22: 13800-
13823.
12. Sol aninejad K, Shadnia S (2014) His o y o he Use and Epidemiology o
O ganophospho us Poisoning. In: Balali-Mood M, Abdollahi M (Eds). Basic
and Clinical Toxicology o O ganophospho us Compounds pp. 25-43.
13. Jokano ic M (2001) Bio ans o ma ion o o ganophospho us compounds.
Toxicology 166: 139-160.
14. Reming on SE (2010) Cellula esponse o DNA damage a e exposu e o
o ganophospha es in i o. BSc (Hons) Medical Biochemis y (Bi mingham
Uni e si y). MSc Toxicology (Bi mingham Uni e si y).
15. Mila o ic D, Gup a RC, Aschne M (2006) An icholines e ase oxici y and
oxida i e s ess. Sci Wo ld J. 6: 295-310.
16. Jokano ić M, Kosano ić M (2010) Neu o oxic e ec s in pa ien s poisoned
wi h o ganophospho us pes icides. En i on Toxicol Pha macol 29: 195-201.
17. Fuku o TR (1990) Mechanism o ac ion o o ganophospho us and ca bama e
insec icides. En i on Heal h Pe spec 87: 245-254.
18. Lee S, Ba on MG (2016) A mechanism-based 3D-QSAR app oach o
classi ica ion and p edic ion o ace ylcholines e ase inhibi o y po ency o
o ganophospha e and ca bama e analogs. J Compu Aided Mol Des 30:
347-363.
19. Jokano ić M, Kosano ić M, B kić D, Vukomano ić P (2011) O ganophospha e
induced delayed polyneu opa hy in man: An o e iew. Clin Neu ol Neu osu g
113: 7-10.
20. Rami ez-Va gas MA, Hue a-Be is ain G, Guzman-Guzman IP, Ala con-
Rome o LD, Flo es-Al a o E, e al. (2017) Me hamidophos induces
cy o oxici y and oxida i e s ess in human pe iphe al blood mononuclea
cells. En i on Toxicol 32: 147-155.
21. Mos a alou S, Abdollahi M (2017) Pes icides: an upda e o human exposu e
and oxici y. A ch Toxicol 91: 549-599.
22. Li F, Xu K, Ni M, Wang B, Gu Z, e al. (2017) E ec o oxida i e
phospho yla ion signaling pa hway on silkwo m midgu ollowing exposu e
o phoxim. En i on Toxicol 32: 167-175.
23. Lukaszewicz-Hussain A (2010) Role o oxida i e s ess in o ganophospha e
insec icide oxici y-Sho e iew. Pes ic Biochem Phys 98: 145-150.
24. And ou sopoulos VP, He nandez AF, Liesi uo i J, Tsa sakis AM (2013)
A mechanis ic o e iew o heal h associa ed e ec s o low le els o
o ganochlo ine and o ganophospho ous pes icides. Toxicology 307: 89-94.
25. Sen hilkuma an B (2015) Pes icide- and sex s e oid analogue-induced
endoc ine dis up ion di e en ially a ge s hypo halamo-hypophyseal-
gonadal sys em du ing game ogenesis in eleos s - A e iew. Gen Comp
Endoc inol 219: 136-142.
26. Walsh LP, Webs e DR, S occo DM (2000) Dime hoa e inhibi s
s e oidogenesis by dis up ing ansc ip ion o he s e oidogenic acu e
egula o y (S AR) gene. J Endoc inol 167: 253-263.
27. Cecchi A, Ro eda i MG, Sabino G, Magna elli GG (2012) En i onmen al
exposu e o o ganophospha e pes icides : Assessmen o endoc ine
dis up ion and hepa o oxici y in p egnan women. Eco oxicol En i on Sa 80:
280-287.
28. Reiss R, Chang ET, Richa dson RJ, Goodman M (2015) A e iew o
epidemiologic s udies o low-le el exposu es o o ganophospho us
insec icides in non-occupa ional popula ions. C i Re Toxicol 45: 531-641.
29. Handal AJ, Ha low SD, B eilh J, Lozo B (2008) Occupa ional exposu e o
pes icides du ing p egnancy and neu obeha io al de elopmen o in an s
and oddle s. Epidemiology 19: 851-859.
30. Young JG, Eskenazi B, Glads one EA, B adman A, Johnson C, e al. (2005)
Ci a ion: Ma in-Reina J, Dua e JA, Ce illos L, Bau is a JD, Mo eno I. Insec icide Rep oduc i e Toxici y P o ile: O ganophospha e, Ca bama e and
Py e h oids. J Toxins. 2017;4(1): 7
J Toxins 4(1): 7 (2017) Page - 07
ISSN: 2328-1723
Associa ion be ween in u e o o ganophospha e pes icide exposu e and
abno mal e lexes in neona es. Neu o oxicology 26: 199-209.
31. Usmani KA, Rose RL, Hodgson E (2003) Inhibi ion and ac i a ion o he
human li e mic osomal and human cy ochome P450 3A4 me abolism o
es os e one by deploymen - ela ed chemicals. D ug Me ab Dispos 31: 384-
391.
32. Naksen W, P apamon ol T, Mangklab uks A, Ryan PB, Riede e AM, e al.
(2015) Associa ions o ma e nal o ganophospha e pes icide exposu e and
PON1 ac i i y wi h bi h ou comes in SAWASDEE bi h coho . En i on Res
142: 288-296.
33. Eskenazi B, Ha ley K, B adman A, Wel zien E, Jewell NP, e al. (2004)
Child en’s Heal h A icle Associa ion o in U e o O ganophospha e Pes icide
Exposu e and Fe al G ow h and Leng h o Ges a ion in an Ag icul u al
Popula ion. En i on Heal h Pe spec 10: 1116-1124.
34. Fishel FM (2011) Pes icide Toxici y P o ile: Chlo ina ed Hyd oca bon
Pes icides. pp. 1-3.
35. Fo de MS, Robe son L, Laouan Sidi EA, Cô é S, Gaud eau E, e al. (2015)
E alua ion o exposu e o o ganophospha e, ca bama e, phenoxy acid, and
chlo ophenol pes icides in p egnan women om 10 Ca ibbean coun ies.
En i on Sci P ocess Impac s 17: 1661-1671.
36. Ca michael SL, Yang W, Robe s E, Kegley SE, B own TJ, e al. (2016)
Residen ial ag icul u al pes icide exposu es and isks o selec ed bi h
de ec s among o sp ing in he San Joaquin Valley o Cali o nia. Bi h
De ec s Res A Clin Mol Te a ol 106: 27-35.
37. Shel on JF, Ge agh y EM, Tanc edi DJ, Delwiche LD, Schmid RJ, e al.
(2014) Neu ode elopmen al diso de s and p ena al esiden ial p oximi y o
ag icul u al pes icides: he CHARGE s udy. En i on Heal h Pe sp 122: 1103-
1109.
38. Mish a D, Tiwa i SK, Aga wal S, Sha ma VP, Cha u edi RK (2012) P ena al
ca bo u an exposu e inhibi s hippocampal neu ogenesis and causes
lea ning and memo y de ici s in o sp ing. Toxicol Sci 127: 84-100.
39. Banji D, Banji OJ, Ragini M, Annamalai AR (2014) Ca bosul an exposu e
du ing emb yonic pe iod can cause de elopmen al disabili y in a s. En i on
Toxicol Pha macol 38: 230-238.
40. Lei W, Wang DD, Dou TY, Hou J, Feng L, e al. (2017) Assessmen o he
inhibi o y e ec s o py e h oids agains human ca boxyles e ases. Toxicol
Appl Pha macol 321: 48-56.
41. B adbe y SM, Cage SA, P oud oo AT, Vale JA (2005) Poisoning due o
py e h oids. Toxicol Re 24: 93-106.
42. U.S Depa men o Heal h and Human Se ices (2003) Toxicological P o ile
Fo Py e h ins And Py e h oids
43. Sha e TJ, Meye DA, C o on KM (2005) De elopmen al neu o oxici y o
py e h oid insec icides : c i ical e iew and u u e esea ch needs. En i on
Heal h Pe spec 113: 123-136.
44. Wakeling EN, Neal AP, A chison WD (2012) Py e h oids and Thei E ec s on
Ion Channels. Pes icides- Ad ances in Chemical and Bo anical Pes icides.
45. Sode lund DM (2012) Molecula mechanisms o py e h oid insec icide
neu o oxici y: ecen ad ances. A ch Toxicol 86: 165-181.
46. Bu SA, Ray DE (2004) S uc u e-Ac i i y and in e ac ion e ec s o 14
di e en py e h oids on ol age-ga ed chlo ide ion channels. Toxicol Sci
346: 341-346.
47. Saillen ai AM, Ndiaye D, Saba é JP (2016) The es ogenic and and ogenic
po en ial o py e h oids in i o. Re iew. Toxicol In Vi o 34: 321-332.
48. Sinha C, Se h K, Islam F, Kuma R, Shukla S, e al. (2006) Beha io al and
neu ochemical e ec s induced by py e h oid-based mosqui o epellen
exposu e in a o sp ings du ing p ena al and ea ly pos na al pe iod.
Neu o oxicol Te a ol 28: 472-481.
49. Imanishi S, Oku a M, Zaha H, Yamamo o T, Akanuma H, e al. (2013)
P ena al exposu e o pe me h in in luences ascula de elopmen o e al
b ain and adul beha io in mice o sp ing. En i on Toxicol 28: 617-629.
50. Qi X, Zheng M, Wu C, Chang X, Wang G, e al. (2011) Impac o p ena al
py e h oid exposu e on neu ode elopmen o one-yea old in an s. Wei
Sheng Yan Jiu 40: 693-697.
51. Dewailly E, Fo de M, Robe son L, Kadda N, Laouan Sidi EA, e al. (2014)
E alua ion o py e h oid exposu es in p egnan women om 10 Ca ibbean
coun ies. En i on In 63: 201-206.
52. Be on T, Mayhoub F, Cha don K, Duca RC, Les emau F, e al. (2014)
De elopmen o an analy ical s a egy based on LC-MS/MS o he
measu emen o di e en classes o pes icides and hei s me aboli es in
meconium: Applica ion and cha ac e isa ion o oe al exposu e in F ance.
En i on Res 132: 311-320.
53. Ding G, Cui C, Chen L, Gao Y, Zhou Y, e al. (2015) P ena al exposu e o
py e h oid insec icides and bi h ou comes in Ru al No he n China. J Expo
Sci En i on Epidemiol 25: 264-270.