[ 2 9] Enviro nme ntal Manage me nt
and He alth 7 / 4 [1996] 2 9 –3 2
© MCB Unive rs ity Pre s s [ISSN 0956-6163]
Experimental studies on reproductive and perinatal
ef fects of lead and cadmium
M artina Piasek
andKrista Kostial
De partme nt o f Mine ral Me tabo lis m, Ins titute fo r Me dic al Re s e arc h and Oc c upatio nal He alth, Z agre b, Re public o f Cro atia, andJohn W. Laskey
Natio nal He alth and Enviro nme ntal Effe c ts Re s e arc h Labo rato ry, US Enviro nme ntal Pro te c tio n Age nc y, No rth Caro lina, USALead is a known reproductive toxicant in humans and ani-mals. Data on cadmium reproductive effects in humans are inconclusive, and in female animals are lacking. More information on the toxicokinetics and toxicity of Pb and Cd during the repro-ductive period and in develop-ing young is needed. Experi-mental studies on rats con-ducted in Laboratories in Croatia and in the USA sepa-rately and as collaborative research show that Pb or Cd have effects on reproductive function. Chronic or sub-chronic oral Pb or Cd expo-sure of the dams causes decreased pup weight and survival, and depressed serum progesterone concen-tration in Cd–exposed dams at the term. No paternally mediated Pb effects were found in offspring. Organ Pb or Cd accumulation was accompanied by changes in essential element concentra-tions in both dam and foetus. Acute in vivo and in vitro exposure to Cd had specifi c effects on gonadal steroido-genesis in both males and females. Proposes possible sites of action of Cd in the steroidogenic pathway.
Significance of overall problem
T h e p r oblem of exp osu r e t o t h e h eav y m et a ls lea d (P b ) a n d ca d m iu m (Cd ) in a ll cou n t r ies a n d t h eir b iologica l effect s h a s b een a sou r ce of gr ow in g con cer n in r ecen t yea r s[1,2]. T h ese m et a ls a r e u b iq u it ou s a n d a r e r elea sed t o t h e en v ir on m en t by h u m a n a ct iv it ies, d e p en d in g on t h e st a ge of in d u st r ia l d evelop -m en t of t h e cou n t r y (e-m ission s fr o-m va r iou s in d u st r ies, sm elt er ies a n d h a za r d ou s w a st e d u m p s).
H u m a n exp osu r e t o P b a n d Cd occu r s fr om occu p a t ion a l sou r ces, en v ir on m en t a lly t h r ou gh t h e food ch a in , a n d Cd fr om ciga r et t e sm ok e. Wom en of ch ild b ea r in g a ge in t h e wor k for ce m ay b e exp osed t o a va r iet y of t oxic su b st a n ces. Com b in ed occu p a t ion a l a n d / or en v ir on m en t a l exp osu r e t o P b a n d / or Cd m ay a dver sely a ffect t h e r e p r od u ct ive h ea lt h of wom en a n d t h e in t er n a l en v ir on -m en t of t h eir d escen d a n t s.
Wit h t h e a p p lica t ion of cu r r en t p u blic h ea lt h r e gu la t ion s, p r e gn a n t wom en ca n n o lon ger b e occu p a t ion a lly exp osed t o P b or Cd , bu t ot h er sou r ces in clu d in g food a n d w a t er con t a m in a t ion , w a ll p a in t , in d u st r ia l w a st es, a u t om ob ile exh a u st fu m es a n d p est icid es a r e yet t o b e elim in a t ed . F u r t h er m or e, wom en a r e gen er a lly u n aw a r e of t h e a dver se effect s of ciga r et t e sm ok e on t h e p la cen t a a n d foet u s, d u e t o it s t oxic con st it u en t s, a m on g w h ich is Cd [3–5]. P op u la t ion gr ou p s, su ch a s wom en of ch ild b ea r in g a ge a n d in fa n t s, w it h t h e lik eli-h ood of d evelop in g n u t r it ion a l d efi cien cy, a r e in a m or e p r eca r iou s p osit ion for t oxic effect s of P b or Cd . T h ey a r e p r on e t o Fe a n d ot h er elem en t d efi cien cies d u e t o t h eir sp ecifi c p h y siologic a n d n u t r it ion a l d em a n d s. An im a l st u d ies h ave sh ow n t h a t p r e gn a n t a n d la ct a t -in g fem a les a n d offsp -in g h ave h igh er -in t est i-n a l a b sor p t ioi-n a i-n d r et ei-n t ioi-n of h eav y m et a ls, w h ich in t er fer e w it h t r a ce elem en t h om eost a -sis[6-8]. Bot h m et a ls a ccu m u la t e in soft t is-su es, in clu d in g or ga n s of t h e r e p r od u ct ive a xis. Over a n in d iv id u a l’s lifet im e, P b is st or ed in b on e a n d t eet h , a n d Cd in t h e k id -n ey. Du r i-n g p r e g-n a -n cy P b m ay b e r elea sed fr om m a t er n a l b on e r eser ves a n d t h u s b ecom e a sou r ce of foet a l exp osu r e[1]. Sim i-la r ly, a n old er m ot h er w it h h igh er Cd b ody bu r d en m ay b e a t h igh er r isk for p la cen t a l Cd
a ccu m u la t ion w it h su b seq u en t a dver se effect s on n u t r it ion of a n u n b or n ch ild [5,9].
Reproductive ef fects of lead and
cadmium
A la r ge b ody of lit er a t u r e clea r ly sh ow s t h a t sever e P b in t oxica t ion is a ssocia t ed w it h st er ilit y a n d m isca r r ia ges. In cr ea ses in n eon a t a l m or t a lit y a n d m or b id it y a lon g w it h d elayed n eu r ot oxic a n d b eh av iou r a l effect s h ave b een r e p or t ed d u e t o h igh p er in a t a l P b exp osu r e[1] Bot h h u m a n a n d a n im a l d a t a sh ow t h a t P b r ea d ily cr osses t h e p la cen t a a n d p r od u ces P b con cen t r a t ion s in t h e n eon a t e com p a r a ble t o t h ose fou n d in m a t er n a l blood .
In con t r a st t o P b r e p r od u ct ive effect s, lim -it ed a n d in con clu sive ev id en ce exist s for a n a ssocia t ion of Cd exp osu r e a n d r e p r od u ct ion in h u m a n fem a les. Recen t d a t a sh ow t h a t Cd a ccu m u la t es in h u m a n ova r ies d e p en d in g on t h e fem a le’s a ge a n d sm ok in g h a b it s[10]. T h er e a r e r e p or t s of h ist ologica l ch a n ges a n d h igh er Cd a ccu m u la t ion in t h e p la cen t a of sm ok in g m ot h er s[11,12]. Low Cd con cen t r a -t ion s m ea su r ed in -t h e h u m a n foe-t u s in d ica -t e t h a t t h e p la cen t a is n ot a com p let e b a r r ier for fet a l Cd exp osu r e[9]. An im a l st u d ies h ave sh ow n t h a t t r a n sfer of essen t ia l t r a ce ele-m en t s (Fe, Zn ) a n d v it a ele-m in s ele-m ay b e in h ib it ed by p la cen t a l Cd a ccu m u la t ion [4].
Related research
Chronic exposure to lead or cadmium
T h e d isp osit ion of h eav y m et a ls h a s b een in vest iga t ed in t h e la b or a t or y in Cr oa t ia for m a n y yea r s. Da t a sh ow ed t h e in fl u en ce of a ge, gen d er, d iet a n d r ou t e of exp osu r e on m et a l toxicok in etics a n d toxicity in th e r a t (e.g. [7,8]).
[ 3 0]
Martina Pias e k, Kris ta Ko s tial and Jo hn W. Las ke y
Expe rime ntal studie s o n re pro duc tive and pe rinatal e ffe c ts o f le ad and c admium
Enviro nme ntal Manage me nt and He alth
7 / 4 [1 9 9 6 ] 2 9 –3 2
Effe c ts o f le ad
At a ll levels of exp osu r e (1,500-7,500 p p m P b ), t h er e w er e n o r e p r od u ct ive effect s in m a le r a t s eva lu a t ed by fer t ilit y in d ex, a n d n u m b er a n d w eigh t of t h e p u p s[13]. At t h e low est con -cen t r a t ion of 1,500 p p m P b, n o effect s w er e fou n d on p u p a p p ea r a n ce a n d v ia b ilit y. E ffect s on n u m b er of live p u p s p er lit t er a n d p u p w eigh t w er e ob ser ved st a r t in g a t 3,500 p p m P b d ose. Re p r od u ct ive P b effect s in fem a le r a t s w er e r ela t ed t o t h e len gt h of exp o-su r e, a n d w er e r ever sible a ft er w it h d r aw a l fr om t h e exp osu r e[14,15]. T h ese r esu lt s a r e in con cor d a n ce w it h fi eld st u d ies con d u ct ed by t h e Cr oa t ia n In st it u t e in a P b -sm elt er y a r ea t h a t sh ow ed a n in cr ea sed r a t e of a b or t ion a n d a d ecr ea se in t h e r a t e of t w in b ir t h s[16].
Ot h er p er in a t a l effect s of P b exp osu r e fou n d in you n g w er e: n e p h r ot oxic (m or p h ologic ch a n ges w it h ch a n ges in elem en t con -cen t r a t ion s in t h e k id n ey ); h a em ot oxic (a n a em ia a n d liver h a em osid er osis w it h “u n u sed ” Fe d u e t o d efect ive h a em oglob in sy n t h esis); a n d h e p a t ot oxic (m or p h ologic ch a n ges in t h e liver )[17-19]. N o d elayed a p p ea r a n ce of t h e P b effect w a s d et ect ed on r en a l fu n ct ion , blood p r essu r e or r e p r od u ct ive in ct e gr ict y in r a ct s exp osed d u r in g p er in a -t a l life[19-21].
Effe c ts o f c admium
Ca d m iu m -r ela t ed effect s on p u p w eigh t a n d Fe st a t u s w it h a n a em ia w er e ob ser ved if exp o-su r e (50 p p m Cd ) st a r t ed eit h er b efor e or a ft er b ir t h [22]. Most sever e effect s w er e ob ser ved in t h e offsp r in g b or n t o t h e d a m s exp osed t o Cd fr om t h e b e gin n in g of gest a t ion , a n d con -t in u ed Cd exp osu r e a f-t er giv in g b ir -t h , i.e., in p r e- p lu s p ost n a t a lly exp osed p u p s. Ca d m iu m a ccu m u la t ion in cr ea sed in d a m s a n d p u p s esp ecia lly d u r in g p er iod of la ct a t ion , w it h con sid er a bly h igh er va lu es of or ga n Cd con -cen t r a t ion s in a d u lt s t h a n in you n g. T h er a py w it h ch ela t in g a gen t [sod iu m –N–(4–m et oxy -b en zy l)–D–glu ca m in e–N–ca r b od it h ioa t e m on oh yd r a t e] a d m in ist er ed a t la ct a t ion d e p let ed Cd st or es m or e efficien t ly in t h e m ot h er s t h a n in offsp r in g[23].
T h e a b ove fi n d in gs a gr ee w it h wor k in t h e colla b or a t in g US la b or a t or y w h ich sh ow ed t h a t Cd a ccu m u la t ed in liver a n d k id n ey m or e r a p id ly w it h exp osu r e d u r in g p r e gn a n cy a n d la ct a t ion (42 d ay s) t h a n w it h sim ila r exp osu r e of n on –p r e gn a n t fem a le r a t s (Sp r a gu eDaw -ley ). E ffect s on t h e r e p r od u ct ive ou t com e in clu d ed a sligh t in cr ea se in p r eim p la n t a t ion d ea t h s a n d a sligh t d ecr ea se in fet a l k id n ey w eigh t w it h a n exp osu r e of 5.0 p p m in t h e d r in k in g w a t er. Ser u m p r ogest er on e (P4) in t h e t er m d a m s w a s d e p r essed r ou gh ly 25 p er cen t [24,25]).
Acute exposure to cadmium
Acu t e in v iv oa n d in v itr ost u d ies on r a t s (Sp r a gu e-Daw ley ) h ave sh ow n t h a t exp osu r e t o sever a l m et a ls, in clu d in g Cd , h a s sp ecifi c effect s on gon a d a l st er oid ogen esis in b ot h m a les a n d fem a les[26-30]. Min ced t est icu la r a n d ova r ia n cu lt u r es h ave b een u sed t o eva lu -a t e P4, t est ost er on e (T), a n d est r a d iol (E2) p r od u ct ion . St er oid p r od u ct ion w a s m ea -su r ed by sp ecifi c r a d ioim u n oa ssay in t h e cu lt u r e m ed iu m a ft er on e t o t h r eeh ou r in cu -b a t ion p er iod s w it h ou t or w it h h CG a n d / or p r ecu r sor su b st r a t e (p r e gn en olon e, a n d r os-t en d ion e or os-t esos-t osos-t er on e) os-t o a ssess os-t h e sios-t e(s) of a ct ion in t h e st er oid ogen ic p a t h w ay.
In m a les, low a cu t e Cd d ose (0.18 m g/ k g s.c.) ca u sed d e p r ession in b ot h st er oid a n d sp er m p r od u ct ion w it h ou t h ist op a t h ologic t est icu -la r ch a n ges[26]. It h a s b een sh ow n in a n in v itr ost u dy t h a t Cd in t er fer es w it h n or m a l Leyd ig cell st er oid ogen esis a t sever a l sit es in t h e b iosy n t h et ic p a t h w ay, a n d r esu lt s in eit h er in h ib it ion or st im u la t ion [28]. It w a s fou n d t h a t Cd2+, Co2+, N i2+, a n d / or Zn2+ion s
in h ib it ed T p r od u ct ion a t sit e(s) p r ior t o ch o-lest er ol sid e ch a in cleava ge, a n d st im u la t ed T p r od u ct ion a t sit e(s) b et w een ch olest er ol sid e ch a in cleava ge a n d t h e d elta5,3 b etah yd r oxy -st er oid d eh yd r ogen a se/d elta-5, d elta-4 iso-m er a se con ver sion of p r e gn en olon e t o P4. In fem a le r a t s, t h e m ost sever e effect s on ova r ia n st er oid ogen esis w er e fou n d w h en t r ea t ed w it h Cd (3 or 5 m g/ k g s.c.) d u r in g p r oest r u s or in ea r ly p r e gn a n cy (d ay 7), w it h t h ose t r ea t ed in t h e la t er st a ge of gest a t ion (d ay 16) r ela t ively u n a ffect ed w h en eva lu a t ed 24 h ou r s follow in g t h e t r ea t m en t . T h e effect s on P4a n d T p r od u ct ion , for t h e m ost p a r t , w er e m od er a t ed by p r ov id in g p r e gn en olon e t o t h e cu lt u r e m ed iu m , w h ile E 2 p r od u ct ion w a s u n a ffect ed [29,30]. Un d er in v itro Cd2+
exp osu r e of t h e r a t ova r y (a ft er in cu b a t ion w it h 0, 100, 500, 1,000, 1,500 a n d 2,000 µM), t h e m ost a ffect ed w er e P4a n d T p r od u ct ion s in p r oest r u s r a t s a n d less in p r e gn a n t d a m s[30]. T h ese fi n d in gs su ggest ed t h a t Cd a ct ed a t sit e(s) p r ior t o ch olest er ol sid e ch a in cleav -a ge, w h ile t h e d e p r ession of T -a n d E2p r od u c-t ion sign ifi ed c-t h e p ossib ilic-t y of oc-t h er sic-t e(s) in t h e ova r ia n st er oid ogen ic p a t h w ay t o b e a ffect ed by Cd .
Recen t st u d ies in p r e gn a n t r a t s d em on -st r a t e t h a t com b in ed n u t r it ion a l Fe
[ 3 1] Martina Pias e k, Kris ta Ko s tial
and Jo hn W. Las ke y Expe rime ntal studie s o n re pro duc tive and pe rinatal e ffe c ts o f le ad and c admium
Enviro nme ntal Manage me nt and He alth
7 / 4 [1 9 9 6 ] 2 9 –3 2
in t h e w h ole foet u s. In exp osed d a m s, Cd con cen t r a t ion w a s or d er ed : k id n ey > liver > blood > > w h ole foet u s. Ca d m iu m effect s in d a m s a n d p u p s w er e gen er a lly d ose-r ela t ed , a n d t h e effect s of com b in ed Cd a n d low Fe exp osu r e w er e lin ea r a n d a d d it ive.
Comment
Where are we with present knowledge?
Du e t o in cr ea sin g en v ir on m en t a l p ollu t ion w it h t oxic m et a ls, r ecogn it ion of t h eir r e p r o-d u ct ive a n o-d p er in a t a l effect s in h u m a n s is essen t ia l. Mor e of t h e wor k on r e p r od u ct ion , d evelop m en t a n d t r a n sp la cen t a l m ovem en t of h eav y m et a ls h a s b een con d u ct ed in a n im a ls t h a n in h u m a n s[32]. Bot h t h e h u m a n a n d a n im a l d a t a sh ow t h a t , in con t r a st t o P b, Cd p a ssa ge a cr oss t h e p la cen t a in t o t h e foet u s is m in im a l. H ow ever, Cd d oes a ccu m u la t e in b ot h t h e h u m a n a n d a n im a l p la cen t a [3,4, 32, 33]. An im a l st u d ies sh ow t h a t Cd a lt er s m icr ocir cu la t ion in r e p r od u ct ive or ga n s, i.e., t est is, ova r y, u t er u s a n d p la cen t a [11,34]. T h er e is lit t le in for m a t ion on t h is p ossib ilit y in h u m a n s. F u r t h er m or e, even for P b, a w ell-k n ow n r e p r od u ct ive t oxica n t , r e p r od u ct ive effect s of ch r on ic low exp osu r e a r e less k n ow n [1]. H u m a n d a t a on P b or Cd m a t er -n a lly m ed ia t ed p er i-n a t a l effect s a r e lim it ed . Da t a on P b or Cd effect s on st er oid ogen esis a r e la ck in g. Mor e h u m a n a n d a n im a l d a t a a r e n eed ed t o elu cid a t e a ssocia t ion (s) b et w een t oxic m et a l con cen t r a t ion s a n d p ot en t ia l en d ocr in e d isr u p t ion (s) in t h e st er oid -p r o-d u cin g or ga n s, i.e., ova r y, t est is a n o-d p la cen t a .
In con clu sion , p r esen t ed r esu lt s sh ow ed t h a t fem a le r a t s a r e m or e su sce p t ible t o t h e r e p r od u ct ive effect of P b. In ca se of Cd , h ow -ever, h igh er d oses w er e r eq u ir ed t o p r od u ce sim ila r ch a n ges in gon a d a l st er oid ogen esis in fem a le t h a n in m a le r a t s. F u t u r e r esea r ch sh ou ld focu s on t h e eva lu a t ion of st er oid h or m on e p r od u ct ion of ova r y a n d p la cen t a in b ot h h u m a n s a n d a n im a ls r ela t ed t o exp osu r e t o t oxic m et a ls. T h e r esu lt s fr om a n im a l st u d -ies sh ou ld b e u sed t o com p a r e t h e effect s in t h e t wo sp ecies, a n d t o p r ov id e a fou n d a t ion for r isk a ssessm en t of r e p r od u ct ive effect s of h eav y m et a ls fr om r od en t st u d ies.
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Martina Pias e k, Kris ta Ko s tial and Jo hn W. Las ke y
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Enviro nme ntal Manage me nt and He alth
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