review article endocrine-disrupting chemicals: some...

Hindawi Publishing CorporationInternational Journal of EndocrinologyVolume 2013 Article ID 828532 9 pageshttpdxdoiorg1011552013828532

Review ArticleEndocrine-Disrupting ChemicalsSome Actions of POPs on Female Reproduction

Ewa L Gregoraszczuk and Anna Ptak

Department of Physiology and Toxicology of Reproduction Institute of Zoology Jagiellonian UniversityGronostajowa 9 30-387 Krakow Poland

Correspondence should be addressed to Ewa L Gregoraszczuk ewagregoraszczukujedupl

Received 7 January 2013 Accepted 26 April 2013

Academic Editor Radmila Kovacevic

Copyright copy 2013 E L Gregoraszczuk and A Ptak This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Persistent organic pollutants (POPs) such as polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) polychlori-nated biphenyls (PCBs) and polybrominated ethers (PBDEs) chloronaftalens (PCNs) and bisphenol A (BPA) are stable lipophilicpollutants that affect fertility and cause serious reproductive problems including ovotoxic action lack of ovulation prematureovarian failure (POF) or polycystic ovarian syndrome (PCOS) Most of the representatives of POPs influence the activation oftranscription factors not only activation of aromatic hydrocarbon receptor (AhR) but also the steroid hormone receptors Thisminireview will focus on a variety of PAH activities in oocyte ovary placenta and mammary gland The complexity and diversityof factors belonging to POPs and disorders of the reproductive function of women indicate that the impact of environmentalpollution as an important determinant factor in fertility should not be minimize

1 Introduction

For the past decade scientists institutions governments andpolicymakers have warned the general public about serioushealth hazards associatedwith chemicals known as endocrinedisruptors (EDs) EDs are exogenous compounds that inter-fere with the synthesis secretion transport metabolismandor action of endogenous hormones that are responsiblefor normal homeostasis reproduction and developmentChemicals with hormonal activity can be divided into threemain groups (i) synthetic compounds used in industry andagriculture as well as in consumer products (ii) syntheticcompounds used in pharmaceutical drugs and (iii) naturalcompounds present in the food chain (ie phytoestrogenscompounds that are structurally similar to estrogen (E2))Only (i) synthetic compounds used in industry and agri-culture and consumer products will be discussed in pre-sented paper Within this class compounds can be fur-ther subcategorized into those that are persistent in all ele-ments of the environment bio-accumulative transporta-ble over long distances and capable of adversely affect-ing life forms that reside within short and long distances

from the site of contamination These compounds includedichlorodiphenyltrichloroethane (DDT a pesticide) poly-chlorinated biphenyls (PCBs) polychlorinated naphthalenes(PCNs) polychlorinated dibenzodioxins (PCDDs) poly-chlorinated dibenzofurans (PCDFs) and polybrominateddiphenyl ethers (PBDEs) (Figure 1)

Because xenobiotics can accumulate in the body for anextremely long period of time (ie decades) they can bedetrimental to human health even at very low doses Forinstance pesticides and other synthetic compounds used inthe 1950s have polluted the air that we breathe the water thatwe drink and the soil that we grow our food in In additionmany of these compounds are nonbiodegradable Studieshave shown the presence of EDS both in adipose tissueand other organs in almost all humans and many animalsHuman exposure to environmental toxicants is mediated viafood and water chains breathing and dermal absorptionwith approximately 90 of the exposure coming from foodMoreover several mammalian organs (eg ovary breastuterus cervix bone muscle and skin) rely on sex steroids fornormal function and these organs are especially vulnerableto endocrine disruption by environmental toxicants This

2 International Journal of Endocrinology

Cl

ClCl

ClCl

(a)

(Cl)119899

(Cl)119899

(b)

(Cl)119899

(c)

O

O (Cl)119899(Cl)

119899

(d)

(Cl)119899(Cl)

119899

O

(e)

O (Br)119899(Br)

119899

(f)

Figure 1 Generic structure of the (a) DDT (b) PCBs (c) PCNs (d)PCDDs (e) PCDFs and (f) PBDEs

chapter will focus only on selected actions or abnormalitiesMuch of the information on the impact of EDs on humanhealth has come from in vivo studies where animals wereexposed to a single compound usually at an acute (iepharmacological) dose however humans are exposed toseveral compounds at unknown concentrations for unknowndurations For example hospital patients receive an averageof six drugs daily (ie aspirin antihistamines antibioticsanti-cough syrup etc) Food and water may also contain lowlevels of organic and inorganic compounds (eg pesticidesand heavy metals) and solvents (eg benzene toluene andchloroform) and air is filledwith hundreds of chemicals (egindustrial pollutants smoke gasoline vapors etc)The abilityof these environmental toxicants to affect human healthdepends on several factors including interactions betweencompounds absorption metabolism accumulation andexcretion of compounds and the ability of some compoundsbind to cell receptors which can affect hormone actionUnfortunately little is known about how these environmental

toxicants interact with each other existing in a mixture It isknown that such xenobiotic acts in different ways dependingon whether their action is observed on the fetus newbornbabies or adult individuals depending on the period duringwhose body has been exposed to these factors Inmany casesthe effect of their actions may be undetected until sexualmaturity especially when exposure occurs during a periodof embryonic development or shortly after birth The femalereproductive cycle is a complex process comprised of game-togenesis embryogenesis menstruation ovulation possi-ble pregnancy endometrial and mammary gland changesDevelopment of the female reproductive system during fetallife determines reproductive success Women are born withall the oocytes they will ever have through their life andtherefore oocytes aremore vulnerable to toxic chemicals thangerm cells in men who continue to make more germ cells

2 Actions on the Oocyte

Oocyte maturation the final step of germ cell differentiationdetermines reproductive capacity Follicles are especially sus-ceptible to the adverse effects of environmental toxicants anddeveloping oocytes may be damaged directly or indirectlyby action on follicular cells (ie granulosa cells) that mayalso be vulnerable to endocrine disruption thereby affectingoocyte function indirectly A previous study illustrated thathuman oocytes harvested from follicles with elevated levelsof polycyclic aromatic hydrocarbons (PCAHs) had fewercell divisions after in vitro fertilization [1] Chloroorganicmixtures such as PCBs and DDT as well as its metaboliteshave also been reported to affect puberty development andoocyte viability adversely [2] Some of these studies pointto unpredictable changes of translational regulation withinthe oocyte under the influence of PCBs [3] Polyspermia(secretion of an excessive amount of semen) has also beendemonstrated in cattle exposed to an environmentally rele-vant mixture of more than 15 organochlorines [4] Presentlyadditional research is needed to better understand themolec-ular mechanisms behind mammalian ovotoxicity caused byexposure to environmental toxicants

Ovarian function is controlled by the hypothalamus pitu-itary and autoparacrine factors Hormone-mimicking com-pounds can bind to cell receptors interfere with hormoneaction and affect ovarian function How EDs affect ovarianfunction is not yet clear but a disruption in gonadotropin(ie follicle stimulating hormone (FSH) and luteinizing hor-mone (LH)) secretion and feedback mechanisms involvingE2 and progesterone (P4) may be involved AlternativelyEDs may affect ovarian hormone production and oocytematuration Damaged oocytes can affect overall hormoneproduction and follicular function resulting in an endocrino-logical imbalance (ie a decrease in E2 and P4 but anincrease in FSH and LH) and ovarian failure

3 Actions on the Ovary

31 Disruption of Ovarian Function Fertility in sexuallymature women depends largely on the maintenance ofhealthy follicles and their steady production ensures that

International Journal of Endocrinology 3

an adequate number of follicles reach the antral stage Thestage of development at which the follicles are destroyeddetermines the influence of these factors on the fertility ofwomen Complete depletion of the follicle reserve results inirreversible infertility partial depletion of the follicle reserveresults in moderate effects on periodicity Damage to largefollicles can also lead to reversible acyclic disorders that affecthormone production and ovulation Nevertheless the effectsof POPs on the hypothalamic-pituitary-ovarian (HPO) axisare generally reversible because they do not permanentlyaffect the follicle reserve

311 TCDD TCDD (2 3 7 8-teterachlorodibenzo-para-dioxin) is an isomer of PCDD and one of the most toxicman-made compounds to pollute our environment Studieson themechanism of TCDD action during ovulation indicatea dysfunction in the HPO axis Misregulation of FSH andLH secretion before ovulation was noted in rats exposed toTCDDMoreover gonadotropin-releasing hormone (GnRH)inhibited the surge in FSH and LH secretion thereby restor-ing ovulation [5 6] TCDD also inhibited FSH secretionand downregulated FSH receptor gene expression [7] TCDDaffected the levels of other hormones as well For instanceGore [8] showed methoxychlor to affect GnRH expressionin hypothalamic GT1-7 cells In a study from our laboratoryTCDD inhibited E2 secretion by follicular cells and P4 secre-tion by luteal cells dose-dependently These adverse effectson hormone production were mediated in part by enzymesinvolved in steroidogenic biosynthesis In luteal cells TCDDaction was independent of E2 receptor stimulation insteadinvolving the aryl hydrocarbon receptor (AhR) [9] On a finalnote other environmental toxicants (ie PCDFs biphenylsDDT and methoxychlor) can also block the surge in LH andFSH secretion during the female reproductive cycle [10 11]

312 PCBs Polychlorinated biphenyls (PCBs) are the man-made chemicals that may disrupt follicular steroidogenesiseither by mimicking natural hormones as agonist or antag-onist altering the pattern of hormone synthesis modulat-ing hormone receptor affinities or numbers or by alteringenzymes involved in hormone secretion In our previousstudy we showed that the orthosubstituted PCB 153 congeneraccumulated preferentially in the follicular wall when com-pared to the nonorthosubstituted PCB 126 congener 71714 and 304 of the total exposure for PCB 153 werein small medium and large follicles respectively (Figure 1)Interestingly about 70 of PCB153 accumulated in earlyantral and antral follicles and only 30 in preovultory fol-liclesThe consequence was a reduction in estradiol secretionby early antral and antral follicles and lack of influence onestradiol secretion by preovulatory follicles Moreover More-over it has been showed that action on estradiol secretionwascorrelatedwith action on aromatase activity [12ndash14] A similardose-responsive relationship was reported after exposure offollicular cells to a mixture of organic pollutants [15] or amixture of PBDEs [16]

313 PBDEs Polybrominated dibenzoethers (PBDEs) arepersistent and ubiquitous environmental toxicants found at

increasing levels in humans and animals Despite recent bansby the European Union [17] United States and China onthe production of penta- and octa-BDE as well as on thediminished use of PBDE in Japan [18] 221015840441015840-tetra-BDE(BDE-47) 2210158404410158405-penta-BDE (BDE-99) and 2210158404410158406-penta-BDE (BDE-100) are themajor PBDE congeners presentin humans and animals [19] The literary data related to theeffects of PBDE mixture are limited predominantly to com-mercial mixture DE-71 which contains mainly penta-BDEs(BDE-99 and BDE-100) and tetra-BDE (BDE-47) Zhou et al[20] and Stoker et al [21] indicated that DE-71 (a mixture ofBDE-99 BDE-100 and tetra-BDE) affected the production ofthyroid and sex steroids and the development of reproductiveorgans [20 21] Results from our laboratory have shownan increase in the P4testosterone (T) ratio but a decreasein the TE2 ratio in ovarian follicles suggesting prematureluteinization of antral follicles Removal of the PBDEmixturefrom cell cultures did not reverse adverse effects [22] In afollow-up study we reported changes in the levels of steroido-genic enzymes (eg 17120573-hydroxysteroid dehydrogenase (17120573-HSD) cytochrome P450 family 17 subfamily A polypeptide1 (CYP17) and aromatase (CYP19)) by PBDE congeners 4799 and 100 [23] Last published data showed fast activationof CYP2B12 and late activation of COMT (with a verylow basal SULT1A activity) in ovarian follicles by BDE-47indicates a possible action of locally produced hydroxylatedmetabolites prior to their detoxification [24] Additionallyit have been showed that 5-OH-BDE-47 and 6-OH-BDE-47have a different mechanism of action in ovarian follicles fromtheir parent compound and lead to an increase in estradiolsecretion The metabolites stimulate aromatase expressionand activity while the parent compound increases androgenproduction and stimulation of 17120573-HSD protein expressionand activity [25]

314 PCNs Polychlorinated naphthalenes (PCNs) are mem-bers of a large and diverse group of compounds with severalindustrial applications PCNs occur as mixtures of congenerssold under various trade names (eg Halowax Nibren Waxand Seekay Wax) [26] The toxicological characteristics ofPCNs are similar to those caused by PCBs PCDDs andPCDFs [27 28] Presently there are little data on the toxicityof PCNs in experimental animals and our recently publisheddata was the first showed direct action on ovarian functionWe showed an increase in basal testosterone secretion in alldoses used with the highest stimulatory action of the smallestdose which was accompanied by a parallel decrease inbasal estradiol secretion induced byHalowax 1051 suggestingandrogenic properties of Halowax 1051 As a mechanism wepropose direct stimulatory action on 17120573-HSD activity andprotein expression enzyme responsible for testosterone syn-thesis and inhibitory action on CYP19 activity and enzymeresponsible for conversion testosterone to estradiol [29] Itshould be taken into consideration that as in the case of BDE-47 [24] the effects of exposure to PCNs may be due to theside effects of PCN metabolites Examining the effects of theHalowax 1051 on phase I (CYP1A1) and phase II (SULT1A andCOMT) enzyme activities and expression in cultured ovarianfollicles we showed fast activation of enzymes involved in


phase I and concurrent inhibition of enzymes involved inphase II metabolism confirming our suggestion that theobserved effects of Halowax 1051 are partially result from theaction of metabolites formed locally in ovarian follicles [30]

315 HCBz Data on the effects of hexachlorobenzene(HCBz) on reproduction are scant While HCBz is toxic tohumans [31 32] and animals [33] information on the effectsof HCBz in ovarian steroidogenesis is limited despite datathat showed an increase in the P4 serum level in superovu-lated rats exposed to HCBz [34] Treatment of Cynomolgusmonkeys with HCBz on the other hand decreased the P4serum level and unaltered the E2 serum level during theluteal phase In a recently published study we determinedin vitro accumulation of hexachlorobenzene (HCBz) andpentachlorobenzene (PeCBz) in porcine ovarian follicles theeffect on steroidogenesis and the expression of enzymesresponsible for steroid synthesis [35] We showed that sixtypercent of the HCBz and almost 100 of the PeCBz that wasadded to the culture medium accumulated in ovarian tissueand only 1 of each was found in the medium Moreover weshowed inhibitory HCBz effect and stimulatory PeCBz effecton testosterone and estradiol secretion As a conclusion wementioned that the greater exposure to an estrogenic actionof PeCBz than antiestrogenic HCBz would be a consequenceof the preferential accumulation of PeCBz in the ovarianfollicles Another situation was observed in human placentaltissue BothHCBz and PeCBz did not accumulate in placentaltissue We showed that HCBz by fast activation of I andII phase metabolism is probably metabolized to PeCBz inplacental tissue (Gregoraszczuk et al unpublished data)

316 A Mixture of Environmental Toxicants Toxicants usu-ally occur in a mixture of several toxicants making it difficultto predict adverse effects onhumanhealth Younglai et al [36]demonstrated human follicular fluid obtained from womento contain 1 1-dichloro-2 2-bis (p-chlorophenyl)-ethylene(p p1015840-DDE) mirex (a pesticide) hexachloro-ethane 1 2 4-trichlorobenzene and numerous PCBs (ie PCBs 49 153 and180) Of these p p1015840-DDE was the most frequently detectedED in follicular fluid and serum Several environmentaltoxicants are ER agonists and they include estrogenic steroids(natural and synthetic) phyto- and mycoestrogens andxenoestrogens (eg pesticides plasticizers and alkylphe-nols) In addition to simple additive effects [37] interactionsbetween different chemicals in a mixture may result in eithera weaker (antagonistic) [38] or stronger (synergistic poten-tiated) combined effect than would be expected from knowl-edge about the toxicity andmode of action of each individualcompound These interactions may occur during toxicantuptake distribution metabolism andor excretion (ie tox-icokinetic phase) or during toxicant binding to receptorsand cellular targets (ie toxicodynamic phase) [39 40] Amixture of xenoestrogens may alter the way a cell responds toendogenous estrogens For instance xenoantiestrogens foundwithin mixtures can inhibit endogenous E2 Moreover someestrogenic compounds exert their effects not by bindingto ER but rather by binding to estrogen plasma transportproteins resulting in an increase in free endogenous E2

Nevertheless mixtures containing both xenoestrogens andendoantiestrogens may have no adverse effects [41] In ourpreviously published data to determine which compoundswithin a PCB-DDT-DDE mixture stimulated E2 secretionwe exposed cells to PCBs 118 138 153 and 180 DDT andDDE alone or in different combinations Interestingly DDTand DDE affected E2 secretion [42] and these results arein agreement with another series of experiments that usedmixtures of PBDEs [43] In the next experiments usingWestern blot analysis indicated that PCBs mixture (ldquoMarinemixrdquo) is an inducer of AhR and mixed-type CYP inducer(CYP1A1 and CYP2B1) while PBDEs mixture (ldquoMjosa mixrdquo)is an inducer of ER120573 and CYP2B [44]

32 Pathology of the Ovary

321 Early Puberty Early puberty is a recent growing con-cern as there are reports of many girls reaching their firstmenstruation and developing breasts earlier in life than wasthe case 40 years ago [45] Early puberty associates withpolycystic ovarian syndrome (PCOS) obesity breast cancerdepression and a number of social challenges such as exper-imentation with sex alcohol or drugs at a younger ageMoreover earlier menarche and thelarche ages have beenreported in girls after exposure to PCBs PBBs DDT andorphthalate esters [46 47] and precocious puberty has beenobserved following exposure to DDT metabolites [48]

322 Polycystic Ovarian Syndrome (PCOS) The acyclicityof the syndrome is linked with the hyperfunctioning oftheca and hypofunctioning of granulosa cells PCOS alsoassociates with other processes (eg neuroendocrine func-tion and ovarian steroidogenesis) and diseases (eg insulinresistance and obesity) that are regulated by hormonal andmetabolic factorsThus exposure to environmental toxicantsmay indeed contribute to the pathogenesis of PCOS Forinstance women with PCOS have higher levels of bisphenolA (BPA a plastics additive) [49] and testosterone which isconsistent with the decreased clearance of BPA that is oftenobserved [50] Although a cause-and-effect relationship hasnot been established the role of environmental toxicants inthe pathogenesis of PCOS is worthy of further consideration

323 Premature Ovarian Failure (POF) POF the cessationof normal ovarian function before the age of 40 occurs inapproximately 1 of women of reproductive age [51] Theunderlying causes of POF are largely known in most casesand any factor that can decrease the ovarian reserve can resultin POF For instance disruption of germ cell migration fromthe genital ridge to the developing gonad results in ovariandysgenesis and POF In addition adult and in utero exposureof mice to BPA resulted in oocyte damage [52 53] whereasexposure of women to cigarette smoke decreased fertility invitro fertilization (IVF) success rates and the ovarian reserveresulted in earlier menopause and increased miscarriagerate [54] In another study exposure of rats to TCDD inutero and throughout reproductive life resulted in prematurereproductive senescence [55] Endocrine disruption causedby acute exposure to environmental toxicants such as the


AhR agonist TCDD suggests that AhR-mediated apoptosis ofoocytes may be involved

4 Hormone-Dependent Cancer

41 Breast Cancer Breast cancer is the most frequent neo-plasm affecting women residing in Western countries and isthe second leading cause of death [56] The general popula-tion is exposed to several hormonally active compounds on adaily basis The majority of these compounds are xenoestro-gens (eg PCAHs pesticides PCBs PBDEs DDT selecteddrugs fungicides phytoestrogens mycotoxins BPA andphthalates) and they can possess estrogenic action affectestrogen levels andor bind to ERs [57]

411 Recent Findings on PCBs The role of PCBs in breastcancer has been investigated intensively Data suggest that acorrelation may exist between high levels of PCBs in mam-mary tissues or sera and breast cancer risk [58] while anotherstudy reported no association [59] High PCB levels upregu-lated CYP expression [60] suggesting that PCB metabolitesmay be critical for the pathogenesis of breast cancer LikewisePang and colleagues [61] reported that exposure of MCF-7human breast cancer cells to PCBs 81 126 and 39 increasedCYP1A1 andCYP1B1mRNA levels resulting in the formationof E2 metabolites We demonstrated PCB 3 to induce and tobe a substrate for CYP1A1in MCF-7 cells [62] On the otherhand others have shown PCBs 52 and 77 to induce oxidativedamage (ie DNA strand breaks) in ER120572 (minus)MDA breastcancer cells but not in ER120572 (+)MCF-7 cells [63] suggestingthat the ER120572 receptormay play a protective role in breast can-cer Moreover PCBs can interfere with the balance betweenproliferation and apoptosis Radice et al [64] demonstratedthose PCB congeners such as PCBs 101 118 138 153 and180 increased proliferations of MCF-7 cells Our publisheddata demonstrated that from investigated congeners (118 138153 and 180) PCB138 and 153 had the highest stimulatoryeffects on basal MCF-7 cell proliferation as well as the highestinhibitory actions on basal caspase-9 activity Moreover weshowed that PCBs 138 and 153 contribute to the action ofendogenous 17120573-estradiol on cell proliferation and apoptosisin the breast cancer cell line MCF-7 [65] In vivo experimentshave also shown PCBs to increasemetastasis by triggering theproduction of reactive oxygen species (ROS) thereby acti-vating the Rho-associated protein kinase (ROCK) signalingpathway [66] or vascular endothelial growth factor (VEGF)overexpression that stimulates endothelial hyperpermeabilityand transendothelial migration of cancer cells [67]

412 Recent Findings on PBDEs Data on the effects of PBDEson breast cancer are scant PBDEs trigger micronucleus for-mation and proliferation in MCF-7 cells [68] An increasein MCF-7 cell proliferation by DE-71 (a mixture of BDE-47 -99 -100 -153 and -154) was also reported by Mercado-Feliciano and Bigsby [69] PBDE-209 also induced MCF-7cell proliferation by affecting critical steps of the cell cycle[70] At the molecular level PBDE-209 triggered proteinkinase C 120572 (PKC120572) and ERK12 phosphorylation On theother hand Kwiecinska et al [71] have shown no changes in

MCF-7 cell proliferation following exposure to BDE-47 -99 -100 and -209 however apoptosis was inhibited by decreasingcaspase-9 activity in these cells [71] Resistance to apoptosisassociates with tumorigenesis as it enables tumorigenic cellsto expand even in a stressful environment Thus additionalstudies are needed to determine if exposure to PBDEs canindeed cause breast cancer

413 Recent Findings on Bisphenol A (BPA) Laboratorystudies in rodents suggest a link between BPA exposure andbreast cancer incidence When rodents were exposed to BPAearly in life there were changes in mammary gland morpho-genesis and tumor susceptibility [72ndash74] These findings aresupported by in vitro data which demonstrated BPA to inducetransformation of MCF-10F human breast cancer cells Thesecells formed tubule-like structures when cultured in 3Dcollagen matrix but spherical masses were noted after BPAtreatment [75] leading the authors to conclude that BPAproduces adducts or ROS which can inadvertently introducea variety of DNAmodifications and cause breast cancer Oth-ers have shown BPA to stimulate proliferation but to inhibitapoptosis inMCF-7 cells [76ndash78] BPAmay also induce breastcancer cell proliferation by upregulating cell cycle genes anddownregulating antiproliferative genes especially genes thatcontrol the G1S transition via ER120572 signaling [79]

42 Ovarian Cancer Ovarian cancer is the most prevalenttype of gynecological cancer affecting women residing inWestern countries As more than 60 of tumors are diag-nosed at stage III and certain forms of cancer are very aggres-sive ovarian cancers are associated with a high mortalityWhile most cells undergo neoplastic transformation includ-ing germ cells granulose and stromal cells approximately90 of tumors are derived from the ovarian surface epithe-lium (OSE) Similar to breast cancer hormonal factors suchas estrogen and xenoestrogens have been linked to ovariancancer [80 81] however the role of environmental toxicantsin ovarian cancer requires further study

421 Recent Findings on PCBs and PBDEs The role ofPCBs in the initiation and progression of ovarian cancer isunknown Studies in adult C57BL mice showed that orallyadministered PBDEs-47 -85 and -99 to accumulate in theliver adrenal cortex and ovary in adult C57BL mice [82]suggest a possible carcinogenic activity especially in light ofresearch showing that exposure of CHO and OVCAR-3 cellsto PBDE-209 initiated S and G2M phases of the cell cyclerespectively [83]

422 Recent Findings on BPA Several in vitro studies haveshown BPA to induce chromosomal aberrations in CHO cells[84 85] a common genetic alteration in cancer Moreoverovarian cyst formation was observed in mice treated neona-tally with BPA [86] Ovarian cancer may stem from incessantovulation which may be linked to the formation of cyststhat are frequently found in perimenopausal women In astudy from our laboratory we demonstrated an increase inproliferation inOVCAR- 3 cells treatedwithBPA Specificallywe showed BPA to promote the cell cycle by upregulating


the expression of cyclin D1 CDK4 E2F1 E2F3 and PCNA(a mediator of G1 to S-phase progression) and cyclin A (amediator of G2-phase progression to mitosis) but by down-regulating the expression of p21WAF1CIP1 Weel-1 andGADD45120572 [87] Additionally we demonstrated a decreasein the expression of proapoptotic genes (ie FAS FADDRAIDD caspase-8 -10 -3 -6 and 7 CAD Bax Bak Bokand Apaf-1) but an increase in the expression of prosurvivalgenes (ie Bcl-x and Mcl-1) BPA also activates a caspases-independent apoptotic pathway by inducing endonuclease Ggene expression Also Hwang et al [88] using microarrayanalysis increased mRNA levels of E2-responsive genes inER-positive ovarian cancer BG-1 cells under the influenceof BPA In a subsequent study we showed BPA to triggerphosphorylation of Stat3 ERK12 and Akt in OVCAR-3cells [89] Cited results of research indicated that BPA actingas a mitogen as well as an antiapoptotic factor may be anadditional factor responsible for ovarian cancer

5 Conclusions

In recent years there has been a growing evidence that expo-sure to chemicals in the environment poses a serious threatto human and animals reproduction via disrupting effectson endocrine function Despite the fact that these substancesare persistent they may be metabolized into more toxiccompounds than the parent molecule in endocrine organsThis endocrine disrupting chemicals (EDCs) adversely affecthealth and reproduction even at very low concentrations andmay exert their effects on the embryo and fetusThe complex-ity and diversity of factors belonging to EDCs its direct actionon the ovary and disorders of the reproductive function ofwomen indicate that the impact of environmental pollutionas an important determinant factor in fertility should notbe minimize Current estimates of cancer risk in humans donot account properly for transplacental and environmental(including occupational) exposure to xenoestrogens It isimportant to reevaluate the role of xenoestrogens in cancerdevelopment using new approaches that better reflect thecomplexity of carcinogenesis Testing new compounds beforethey are allowed to use should be expanded to determinetheir effect on the endocrine system in order to assess thehormonal activity In addition attention should be directedtowards dose-response relationships in environmental tox-icology Such studies can provide useful information thatmight have a significant impact on the strategies for riskassessment of toxic substances

Acknowledgment

This research is supported by KZDS002592 JagiellonianUniversity in Cracow Poland

References

[1] P Pocar T A L Brevini B Fischer and FGandolfi ldquoThe impactof endocrine disruptors on oocyte competencerdquo Reproductionvol 125 no 3 pp 313ndash325 2003

[2] C Campagna M A Sirard P Ayotte and J L Bailey ldquoIm-paired maturation fertilization and embryonic development

of porcine oocytes following exposure to an environmentallyrelevant organochlorine mixturerdquo Biology of Reproduction vol65 no 2 pp 554ndash560 2001

[3] P Pocar T A L Brevini F Perazzoli F Cillo S Modina and FGandolfi ldquoCellular and molecular mechanisms mediating theeffects of polychlorinated biphenyls on oocyte developmentalcompetence in Cattlerdquo Molecular Reproduction and Develop-ment vol 60 no 4 pp 535ndash541 2001

[4] CCampagna CGuillemette R ParadisMA Sirard P Ayotteand J L Bailey ldquoAn environmentally relevant organochlorinemixture impairs sperm function and embryo development inthe porcine modelrdquo Biology of Reproduction vol 67 no 1 pp80ndash87 2002

[5] B Eskenazi M Warner P Mocarelli et al ldquoSerum dioxinconcentrations and menstrual cycle characteristicsrdquo AmericanJournal of Epidemiology vol 156 no 4 pp 383ndash392 2002

[6] X Gao B K Petroff K K Rozman and P F Terranova ldquoGon-adotropin-releasing hormone (GnRH) partially reverses theinhibitory effect of 2378-tetrachlorodibenzo-p-dioxin on ovu-lation in the immature gonadotropin-treated ratrdquo Toxicologyvol 147 no 1 pp 15ndash22 2000

[7] T Hirakawa T Minegishi K Abe et al ldquoEffect of 2378-tetrachlorodibenzo-p-dioxin on the expression of follicle-stimulating hormone receptors during cell differentiation incultured granulosa cellsrdquo Endocrinology vol 141 no 4 pp1470ndash1476 2000

[8] A C Gore ldquoOrganochlorine pesticides directly regulate gona-dotropin-releasing hormone gene expression and biosynthesisin the GT1-7 hypothalamic cell linerdquo Molecular and CellularEndocrinology vol 192 no 1-2 pp 157ndash170 2002

[9] E L Gregoraszczuk E Zabielny and D Ochwat ldquoAryl hydro-carbon receptor (AhR)-linked inhibition of luteal cell proges-terone secretion in 2378-tetrachlorodibenzo-p-dioxin treatedcellsrdquo Journal of Physiology and Pharmacology vol 52 no 2 pp303ndash311 2001

[10] X Gao P F Terranova and K K Rozman ldquoEffects of poly-chlorinated dibenzofurans biphenyls and their mixture withdibenzo-p-dioxins on ovulation in the gonadotropin-primedimmature rat support for the toxic equivalency conceptrdquoToxicology and Applied Pharmacology vol 163 no 2 pp 115ndash124 2000

[11] K Okazaki S Okazaki S Nishimura et al ldquoA repeated 28-dayoral dose toxicity study of methoxychlor in rats based on theldquoenhanced OECD test guideline 407rdquo for screening endocrine-disrupting chemicalsrdquo Archives of Toxicology vol 75 no 9 pp513ndash521 2001

[12] E L Gregoraszczuk A Grochowalski R Chrzaszcz and MWegiel ldquoCongener-specific accumulation of polychlorinatedbiphenyls in ovarian follicular wall follows repeated exposureto PCB 126 and PCB 153 Comparison of tissue levels of PCBand biological changesrdquo Chemosphere vol 50 no 4 pp 481ndash488 2003

[13] A K Wojtowicz E Ropstad and E L Gregoraszczuk ldquoEstrouscycle-dependent changes in steroid secretion by pig ovariancells exposed in vitro to polychlorinated biphenyl (PCB 153)rdquoEndocrine Regulations vol 35 no 4 pp 223ndash228 2001

[14] E L Gregoraszczuk M Sowa M Kajta A Ptak and AWojtowicz ldquoEffect of PCB 126 and PCB 153 on incidence ofapoptosis in cultured theca and granulosa cells collected fromsmall medium and large preovulatory folliclesrdquo ReproductiveToxicology vol 17 no 4 pp 465ndash471 2003


[15] E L Gregoraszczuk K Milczarek A K Wojtowicz V Berg JU Skaare andE Ropstad ldquoSteroid secretion following exposureof ovarian follicular cells to three different natural mixtures ofpersistent organic pollutants (POPs)rdquo Reproductive Toxicologyvol 25 no 1 pp 58ndash66 2008

[16] BSEF ldquoBromine science and enviromental forumrdquo 2007 httpwwwbsefcom

[17] K Akutsu and S Hori ldquoPolybrominated diphenyl ether flameretardants in foodstuffs and human milkrdquo Shokuhin EiseigakuZasshi vol 45 no 4 pp 175ndash183 2004

[18] I A T M Meerts R J Letcher S Hoving et al ldquoIn vitroestrogenicity of polybrominated diphenyl ethers hydroxylatedPBDEs and polybrominated bisphenol A compoundsrdquo Envi-ronmental Health Perspectives vol 109 no 4 pp 399ndash407 2001

[19] A Sjodin D G Patterson Jr and A Bergman ldquoA review onhuman exposure to brominated flame retardantsmdashparticularlypolybrominated diphenyl ethersrdquo Environment Internationalvol 29 no 6 pp 829ndash839 2003

[20] T Zhou M M Taylor M J De Vito and K M CroftonldquoDevelopmental exposure to brominated diphenyl ethers resultsin thyroid hormone disruptionrdquo Toxicological Sciences vol 66no 1 pp 105ndash116 2002

[21] T E Stoker S C Laws K M Crofton J M Hedge J MFerrell and R L Cooper ldquoAssessment of DE-71 a commercialpolybrominated diphenyl ether (PBDE) mixture in the EDSPmale and female pubertal protocolsrdquo Toxicological Sciences vol78 no 1 pp 144ndash155 2004

[22] A Karpeta and E L Gregoraszczuk ldquoMixture of dominantPBDE congeners (BDE-47 -99 -100 and -209) at levels notedin human blood dramatically enhances progesterone secretionby ovarian folliclesrdquo Endocrine Regulations vol 44 no 2 pp49ndash55 2010

[23] A Karpeta A Rak-Mardyła J Jerzak and E L GregoraszczukldquoCongener-specific action of PBDEs on steroid secretionCYP17 17120573-HSD and CYP19 activity and protein expression inporcine ovarian folliclesrdquo Toxicology Letters vol 206 pp 258ndash263 2011

[24] A Karpeta K Warzecha J Jerzak A Ptak and E L Grego-raszczuk ldquoActivation of the enzymes of phase I (CYP2B12)and phase II (SULT1A and COMT) metabolism by 2 21015840 4 41015840-tetrabromodiphenyl ether (BDE47) in the pig ovaryrdquo Reproduc-tive Toxicology vol 34 pp 436ndash442 2012

[25] A Karpeta J Barc and A Ptak ldquoGregoraszczuk ELThe 2 21015840 441015840-tetrabromodiphenyl ether hydroxylated metabolites 5-OH-BDE-47 and 6-OH-BDE-47 stimulate estradiol secretion in theovary by activating aromatase expressionrdquo Toxicology vol 305pp 65ndash70 2013

[26] J Falandysz ldquoChloronaphthalenes as food-chain contaminantsa reviewrdquo Food Additives and Contaminants vol 21 pp 995ndash1014 2003

[27] A L Blankenship K Kannan S A Villalobos et al ldquoRela-tive potencies of individual polychlorinated naphthalenes andhalowax mixtures to induce Ah receptor-mediated responsesrdquoEnvironmental Science and Technology vol 34 no 15 pp 3153ndash3158 2000

[28] D L Villeneuve K Kannan J S Khim et al ldquoRelative potenciesof individual polychlorinated naphthalenes to induce dioxin-like responses in fish and mammalian in vitro bioassaysrdquoArchives of Environmental Contamination and Toxicology vol39 no 3 pp 273ndash281 2000

[29] E Ł Gregoraszczuk J Jerzak A Rak-Mardyła and J FalandyszldquoHalowax 1051 affects steroidogenesis 17120573-hydroxysteroid

dehydrogenase (17120573-HSD) and cytochrome P450arom (CYP19)activity and protein expression in porcine ovarian folliclesrdquoReproductive Toxicology vol 32 pp 379ndash384 2011

[30] J Barc A Karpeta and E L Gregoraszczuk ldquoAction of halowax1051 on enzymes of phase I (CYP1A1) and phase II (SULT1Aand COMT)metabolism in the pig ovaryrdquo International Journalof Endocrinology vol 2013 Article ID 590261 7 pages 2013

[31] J F Jarrell A Gocmen D Akyol and R Brant ldquoHexachlorob-enzene exposure and the proportion of male births in Turkey1935ndash1990rdquo Reproductive Toxicology vol 16 no 1 pp 65ndash702002

[32] N Khanjani and M R Sim ldquoReproductive outcomes ofmaternal contamination with cyclodiene insecticides hex-achlorobenzene and 120573-benzene hexachloriderdquo Science of theTotal Environment vol 368 no 2-3 pp 557ndash564 2006

[33] L Alvarez A Randi P Alvarez et al ldquoReproductive effects ofhexachlorobenzene in female ratsrdquo Journal of Applied Toxicol-ogy vol 20 pp 81ndash87 2000

[34] W G Foster J A Pentick A McMahon and P R LecavalierldquoOvarian toxicity of hexachlorobenzene (HCB) in the super-ovulated female ratrdquo Journal of Biochemical Toxicology vol 7no 1 pp 1ndash4 1992

[35] E Ł Gregoraszczuk A Ptak A Rak-Mardyła and J FalandyszldquoDifferential accumulation of HCBz and PeCBz in porcineovarian follicles and their opposing actions on steroid secretionand CYP11 CYP17 17120573-HSD and CYP19 protein expression Atissue culture approachrdquo Reproductive Toxicology vol 31 no 4pp 494ndash499 2011

[36] E V Younglai W G Foster E G Hughes K Trim and J FJarrell ldquoLevels of environmental contaminants in human follic-ular fluid serum and seminal plasma of couples undergoingin vitro fertilizationrdquo Archives of Environmental Contaminationand Toxicology vol 43 no 1 pp 121ndash126 2002

[37] K Ramamoorthy C Vyhlidal F Wang et al ldquoAdditive estro-genic activities of a binary mixture of 210158404101584061015840-Trichloro- and21015840310158404101584051015840-tetrachloro-4-biphenylolrdquo Toxicology and AppliedPharmacology vol 147 no 1 pp 93ndash100 1997

[38] K C Donnelly L D Claxton H J Huebner and J L CapizzildquoMutagenic interactions of model chemical mixturesrdquo Chemo-sphere vol 37 no 7 pp 1253ndash1261 1998

[39] S A Andric T S Kostic S S Stojilkovic and R Z KovacevicldquoInhibition of rat testicular androgenesis by a polychlorinatedbiphenylmixtureAroclor 1248rdquoBiology of Reproduction vol 62no 6 pp 1882ndash1888 2000

[40] E J Calabrese and L A Baldwin ldquoHormesis U-shaped doseresponses and their centrality in toxicologyrdquo Trends in Pharma-cological Sciences vol 22 no 6 pp 285ndash291 2001

[41] D O Carpenter K Arcaro and D C Spink ldquoUnderstandingthe human health effects of chemical mixturesrdquo EnvironmentalHealth Perspectives vol 110 no 1 pp 25ndash42 2002

[42] E L Gregoraszczuk A Ptak M Karniewska and E RopstadldquoAction of definedmixtures of PCBs pp1015840-DDT and its metabo-lite pp1015840-DDE on co-culture of porcine theca and granulosacells steroid secretion cell proliferation and apoptosisrdquo Repro-ductive Toxicology vol 26 no 2 pp 170ndash174 2008

[43] E Ł Gregoraszczuk A Rak K Kawalec and E RopstadldquoSteroid secretion following exposure of ovarian follicular cellsto single congeners and defined mixture of polybrominated-dibenzoethers (PBDEs) pp1015840-DDT and its metabolite pp1015840-DDErdquo Toxicology Letters vol 178 no 2 pp 103ndash109 2008

[44] E L Gregoraszczuk A Ptak J U Skaare et al ldquoMechanismsof action of two different natural mixtures of persistent organic


pollutants (POPs) in ovarian folliclesrdquo Xenobiotica vol 39 no1 pp 80ndash89 2009

[45] E Diamanti-Kandarakis J P Bourguignon L C Giudice et alldquoEndocrine-disrupting chemicals an endocrine society scien-tific statementrdquo Endocrine Reviews vol 30 no 4 pp 293ndash3422009

[46] E Den Hond G Schoeters W G Sippell et al ldquoEndocrine dis-rupters and human pubertyrdquo International Journal of Andrologyvol 29 no 1 pp 264ndash271 2006

[47] I ColonDCaro C J Bourdony andORosario ldquoIdentificationof phthalate esters in the serum of young Puerto Rican girlswith premature breast developmentrdquo Environmental HealthPerspectives vol 108 no 9 pp 895ndash900 2000

[48] M Krstevska-Konstantinova C Charlier M Craen et alldquoSexual precocity after immigration from developing countriesto Belgium evidence of previous exposure to organochlorinepesticidesrdquo Human Reproduction vol 16 no 5 pp 1020ndash10262001

[49] T Takeuchi O Tsutsumi Y Ikezuki Y Takai and Y TaketanildquoPositive relationship between androgen and the endocrinedisruptor bisphenol A in normal women and women withovarian dysfunctionrdquo Endocrine Journal vol 51 no 2 pp 165ndash169 2004

[50] T Takeuchi O Tsutsumi Y Ikezuki et al ldquoElevated serumbisphenol A levels under hyperandrogenic conditions maybe caused by decreased UDP-glucuronosyltransferase activityrdquoEndocrine Journal vol 53 no 4 pp 485ndash491 2006

[51] P Sinha and N Kuruba ldquoPremature ovarian failurerdquo Journal ofObstetrics and Gynaecology vol 27 no 1 pp 16ndash19 2007

[52] P A Hunt K E Koehler M Susiarjo et al ldquoBisphenol aexposure causes meiotic aneuploidy in the female mouserdquoCurrent Biology vol 13 no 7 pp 546ndash553 2003

[53] M Susiarjo T J Hassold E Freeman and P A Hunt ldquoBisphe-nol A exposure in utero disrupts early oogenesis in the mouserdquoPLoS Genetics vol 3 no 1 article e5 2007

[54] S J Genuis ldquoHealth issues and the environment-an emergingparadigm for providers of obstetrical and gynaecological healthcarerdquo Human Reproduction vol 21 pp 2201ndash2208 2006

[55] Z Shi K E Valdez A Y Ting A Franczak S L Gum and BK Petroff ldquoOvarian endocrine disruption underlies prematurereproductive senescence following environmentally relevantchronic exposure to the aryl hydrocarbon receptor agonist2378-tetrachlorodibenzo-p-dioxinrdquo Biology of Reproductionvol 76 no 2 pp 198ndash202 2007

[56] J V Lacey Jr S S Devesa and L A Brinton ldquoRecent trendsin breast cancer incidence and mortalityrdquo Environmental andMolecular Mutagenesis vol 39 no 2-3 pp 82ndash88 2002


[58] R Recio-Vega V Velazco-Rodriguez G Ocampo-Gomez SHernandez-Gonzalez P Ruiz-Flores and F Lopez-MarquezldquoSerum levels of polychlorinated biphenyls in Mexican womenand breast cancer riskrdquo Journal of Applied Toxicology vol 31 no3 pp 270ndash278 2011

[59] J A Rusiecki T R Holford S H Zahm and T Zheng ldquoPoly-chlorinated biphenyls and breast cancer risk by combinedestrogen and progesterone receptor statusrdquo European Journal ofEpidemiology vol 19 no 8 pp 793ndash801 2004

[60] F Laden N Ishibe S E Hankinson et al ldquoPolychlorinatedbiphenyls cytochrome P450 1A1 and breast cancer risk in theNursesrsquo Health Studyrdquo Cancer Epidemiology Biomarkers andPrevention vol 11 no 12 pp 1560ndash1565 2002

[61] S Pang J Q Cao B H Katz C L Hayes T R Sutter andD C Spink ldquoInductive and inhibitory effects of non-ortho-substituted polychlorinated biphenyls on estrogen metabolismand human cytochromes P450 1A1 and 1B1rdquo Biochemical Phar-macology vol 58 no 1 pp 29ndash38 1999

[62] A Ptak G Ludewig A Rak W Nadolna M Bochenek and EL Gregoraszczuk ldquoInduction of cytochrome P450 1A1 inMCF-7 human breast cancer cells by 4-chlorobiphenyl (PCB3) andthe effects of its hydroxylatedmetabolites on cellular apoptosisrdquoEnvironment International vol 36 no 8 pp 935ndash941 2010

[63] C H Lin C L Huang M C Chuang et al ldquoProtective roleof estrogen receptor-alpha on lower chlorinated PCB congener-induced DNA damage and repair in human tumoral breastcellsrdquo Toxicology Letters vol 188 no 1 pp 11ndash19 2009

[64] S Radice E Chiesara S Fucile and L Marabini ldquoDifferenteffects of PCB101 PCB118 PCB138 and PCB153 alone or mixedin MCF-7 breast cancer cellsrdquo Food and Chemical Toxicologyvol 46 no 7 pp 2561ndash2567 2008

[65] A Ptak K Mazur and E L Gregoraszczuk ldquoComparison ofcombinatory effects of PCBs (118 138 153 and 180) with 17 120573-estradiol on proliferation and apoptosis inMCF-7 breast cancercellsrdquoToxicology and IndustrialHealth vol 27 no 4 pp 315ndash3212011

[66] S Liu S Li and Y Du ldquoPolychlorinated biphenyls (PCBs)enhance metastatic properties of breast cancer cells by activat-ing rho-associated kinase (ROCK)rdquo PLoS ONE vol 5 no 6Article ID e11272 2010

[67] S Y Eum Y W Lee B Hennig and M Toborek ldquoVEGFregulates PCB 104-mediated stimulation of permeability andtransmigration of breast cancer cells in human microvascularendothelial cellsrdquo Experimental Cell Research vol 296 no 2 pp231ndash244 2004

[68] J L Barber M J Walsh R Hewitt K C Jones and F LMartin ldquoLow-dose treatment with polybrominated diphenylethers (PBDEs) induce altered characteristics in MCF-7 cellsrdquoMutagenesis vol 21 no 5 pp 351ndash360 2006

[69] M Mercado-Feliciano and R M Bigsby ldquoThe polybrominateddiphenyl ether mixture DE-71 ls Mildly estrogenicrdquo Environ-mental Health Perspectives vol 116 no 5 pp 605ndash611 2008

[70] Z H Li X Y Liu N Wang et al ldquoEffects of decabrominateddiphenyl ether (PBDE-209) in regulation of growth and apop-tosis of breast ovarian and cervical cancer cellsrdquoEnvironmentalHealth Perspectives vol 120 pp 541ndash546 2012

[71] P Kwiecinska A Wrobel and E Ł Gregoraszczuk ldquoCom-binatory effects of PBDEs and 17120573-estradiol on MCF-7 cellproliferation and apoptosisrdquo Pharmacological Reports vol 63pp 189ndash194 2011

[72] T J Murray M V Maffini A A Ucci C Sonnenschein andA M Soto ldquoInduction of mammary gland ductal hyperplasiasand carcinoma in situ following fetal bisphenol A exposurerdquoReproductive Toxicology vol 23 no 3 pp 383ndash390 2007

[73] M Durando L Kass J Piva et al ldquoPrenatal bisphenol Aexposure induces preneoplastic lesions in the mammary glandin wistar ratsrdquo Environmental Health Perspectives vol 115 no 1pp 80ndash86 2007

[74] R A Keri S M Ho P A Hunt K E Knudsen A M Sotoand G S Prins ldquoAn evaluation of evidence for the carcinogenic


activity of bisphenol Ardquo Reproductive Toxicology vol 24 no 2pp 240ndash252 2007

[75] S V Fernandez and J Russo ldquoEstrogen and Xenoestrogens inbreast cancerrdquo Toxicologic Pathology vol 38 no 1 pp 110ndash1222010

[76] C M Olsen E T M Meussen-Elholm M Samuelsen J AHolme and J K Hongslo ldquoEffects of the environmental oestro-gens bisphenolA tetrachlorobisphenolA tetrabromobisphenolA 4-hydroxybiphenyl and 441015840-dihydroxybiphenyl on oestro-gen receptor binding cell proliferation and regulation of oestro-gen sensitive proteins in the human breast cancer cell lineMCF-7rdquo Pharmacology and Toxicology vol 92 no 4 pp 180ndash1882003

[77] A Ricupito G Del Pozzo N Diano et al ldquoEffect of bisphenolA with or without enzyme treatment on the proliferation andviability of MCF-7 cellsrdquo Environment International vol 35 no1 pp 21ndash26 2009

[78] P Diel S Olff S Schmidt and H Michna ldquoEffects of the envi-ronmental estrogens bisphenolA op1015840-DDT p-tert-octylphenoland coumestrol on apoptosis induction cell proliferation andthe expression of estrogen sensitivemolecular parameters in thehuman breast cancer cell line MCF-7rdquo Journal of Steroid Bio-chemistry and Molecular Biology vol 80 no 1 pp 61ndash70 2002

[79] H R Lee K A Hwang M A Park B R Yi E B Jeung and KC Choi ldquoTreatmentwith bisphenol A andmethoxychlor resultsin the growth of human breast cancer cells and alteration of theexpression of cell cycle-related genes cyclin D1 and p21 via anestrogen receptor-dependent signaling pathwayrdquo InternationalJournal of Molecular Medicine vol 29 pp 883ndash890 2012

[80] V Bencko ldquoHuman exposure to endocrine disrupters carcino-genic risk assessmentrdquo Folia Histochemica et Cytobiologica vol39 no 2 pp 24ndash25 2001

[81] T A L Brevini S B Zaneto and F Cillo ldquoEffects of endocrinedisruptors on developmental and reproductive functionsrdquo Cur-rent Drug Targets vol 5 no 1 pp 1ndash10 2005

[82] P O Darnerud and S Risberg ldquoTissue localisation of tetra- andpentabromodiphenyl ether congeners (BDE-47 -85 and -99) inperinatal and adult C57BL micerdquo Chemosphere vol 62 no 3pp 485ndash493 2006

[83] C E Talsness S N Kuriyama A Sterner-Kock et al ldquoIn uteroand lactational exposures to low doses of polybrominateddiphenyl ether-47 alter the reproductive system and thyroidgland of female rat offspringrdquo Environmental Health Perspec-tives vol 116 no 3 pp 308ndash314 2008

[84] C A Hilliard M J Armstrong C I Bradt R B Hill S KGreenwood and S M Galloway ldquoChromosome aberrations invitro related to cytotoxicity of nonmutagenic chemicals andmetabolic poisonsrdquo Environmental and Molecular Mutagenesisvol 31 pp 316ndash326 1998

[85] S M Galloway J E Miller M J Armstrong C L Bean T RSkopek and W W Nichols ldquoDNA synthesis inhibition as anindirect mechanism of chromosome aberrations comparisonof DNA-reactive and non-DNA-reactive clastogensrdquo MutationResearch vol 400 no 1-2 pp 169ndash186 1998

[86] R R Newbold W N Jefferson and E Padilla-Banks ldquoLong-term adverse effects of neonatal exposure to bisphenol A on themurine female reproductive tractrdquoReproductive Toxicology vol24 no 2 pp 253ndash258 2007

[87] A Ptak A Wrobel and E L Gregoraszczuk ldquoEffect of bisphe-nol-A on the expression of selected genes involved in cell cycleand apoptosis in the OVCAR-3 cell linerdquo Toxicology Letters vol202 no 1 pp 30ndash35 2011

[88] K A Hwang S H Park B R Yi and K C Choi ldquoGene alter-ations of ovarian cancer cells expressing estrogen receptors byestrogen and bisphenol a usingmicroarray analysisrdquo LaboratoryAnimal Research vol 27 pp 99ndash107 2011

[89] A Ptak and E L Gregoraszczuk ldquoBisphenol A induces leptinreceptor expression creating more binding sites for leptin andactivates the JAKStat MAPKERK and PI3KAkt signallingpathways in human ovarian cancer cellrdquo Toxicology Letters vol210 pp 332ndash337 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Cl

ClCl

ClCl

(a)

(Cl)119899

(Cl)119899

(b)

(Cl)119899

(c)

O

O (Cl)119899(Cl)

119899

(d)

(Cl)119899(Cl)

119899

O

(e)

O (Br)119899(Br)

119899

(f)

Figure 1 Generic structure of the (a) DDT (b) PCBs (c) PCNs (d)PCDDs (e) PCDFs and (f) PBDEs

chapter will focus only on selected actions or abnormalitiesMuch of the information on the impact of EDs on humanhealth has come from in vivo studies where animals wereexposed to a single compound usually at an acute (iepharmacological) dose however humans are exposed toseveral compounds at unknown concentrations for unknowndurations For example hospital patients receive an averageof six drugs daily (ie aspirin antihistamines antibioticsanti-cough syrup etc) Food and water may also contain lowlevels of organic and inorganic compounds (eg pesticidesand heavy metals) and solvents (eg benzene toluene andchloroform) and air is filledwith hundreds of chemicals (egindustrial pollutants smoke gasoline vapors etc)The abilityof these environmental toxicants to affect human healthdepends on several factors including interactions betweencompounds absorption metabolism accumulation andexcretion of compounds and the ability of some compoundsbind to cell receptors which can affect hormone actionUnfortunately little is known about how these environmental

toxicants interact with each other existing in a mixture It isknown that such xenobiotic acts in different ways dependingon whether their action is observed on the fetus newbornbabies or adult individuals depending on the period duringwhose body has been exposed to these factors Inmany casesthe effect of their actions may be undetected until sexualmaturity especially when exposure occurs during a periodof embryonic development or shortly after birth The femalereproductive cycle is a complex process comprised of game-togenesis embryogenesis menstruation ovulation possi-ble pregnancy endometrial and mammary gland changesDevelopment of the female reproductive system during fetallife determines reproductive success Women are born withall the oocytes they will ever have through their life andtherefore oocytes aremore vulnerable to toxic chemicals thangerm cells in men who continue to make more germ cells

2 Actions on the Oocyte

Oocyte maturation the final step of germ cell differentiationdetermines reproductive capacity Follicles are especially sus-ceptible to the adverse effects of environmental toxicants anddeveloping oocytes may be damaged directly or indirectlyby action on follicular cells (ie granulosa cells) that mayalso be vulnerable to endocrine disruption thereby affectingoocyte function indirectly A previous study illustrated thathuman oocytes harvested from follicles with elevated levelsof polycyclic aromatic hydrocarbons (PCAHs) had fewercell divisions after in vitro fertilization [1] Chloroorganicmixtures such as PCBs and DDT as well as its metaboliteshave also been reported to affect puberty development andoocyte viability adversely [2] Some of these studies pointto unpredictable changes of translational regulation withinthe oocyte under the influence of PCBs [3] Polyspermia(secretion of an excessive amount of semen) has also beendemonstrated in cattle exposed to an environmentally rele-vant mixture of more than 15 organochlorines [4] Presentlyadditional research is needed to better understand themolec-ular mechanisms behind mammalian ovotoxicity caused byexposure to environmental toxicants

Ovarian function is controlled by the hypothalamus pitu-itary and autoparacrine factors Hormone-mimicking com-pounds can bind to cell receptors interfere with hormoneaction and affect ovarian function How EDs affect ovarianfunction is not yet clear but a disruption in gonadotropin(ie follicle stimulating hormone (FSH) and luteinizing hor-mone (LH)) secretion and feedback mechanisms involvingE2 and progesterone (P4) may be involved AlternativelyEDs may affect ovarian hormone production and oocytematuration Damaged oocytes can affect overall hormoneproduction and follicular function resulting in an endocrino-logical imbalance (ie a decrease in E2 and P4 but anincrease in FSH and LH) and ovarian failure

3 Actions on the Ovary

31 Disruption of Ovarian Function Fertility in sexuallymature women depends largely on the maintenance ofhealthy follicles and their steady production ensures that






























5 Conclusions


Acknowledgment


References






































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of













































5 Conclusions


Acknowledgment


References






































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article endocrine-disrupting chemicals: some...

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