Insecticide Reproductive Toxicity Profile: Organophosphate, Carbamate and Pyrethroids

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. 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