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Impacts of Phthalate Plasticisers—An Emerging Issues and Concerns

Fathima Shincy, K C Chitra

Abstract


Phthalates or phthalic acid esters are the esters of phthalic anhydride used to increase the flexibility and durability of plastic products including polyvinyl chloride (PVC). Based on the molecular weight, phthalates are grouped into low and high phthalates that shows diverse applications and different mode of toxicity in various animals. The enormous production and widespread applications allow them to exist in all environments including air, water, and soil; in solid, liquid and gaseous samples as well as in fat and biological samples. The current review stated an overview on the contribution of phthalates on adverse developmental, behavioural, transgenerational, physiological, cytogenetic, neurotoxic, immunological, metabolic, hormonal, histological and reproductive effects in various animals. Since plasticizers have become an integral part of our daily life, recycling of phthalates from households and industries must be promoted to prevent an additional production and frequent discharge into the environment.

Keywords


Phthalates; Plasticisers; Applications; Types; Toxic effects

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References


Wang WL, Wu QY, Wang C, He T, Hu HY. Health risk assessment of phthalate esters (PAEs) in drinking water sources of China. Environ Sci Pollut Res Int. 2015; 22(5):3620-3630. doi:10.1007/s11356-014-3615-z.

Babich MA, Bevington C, Dreyfus MA. Plasticizer migration from children's toys, child care articles, art materials, and school supplies. Regul Toxicol Pharmacol. 2020; 111:104574. doi:10.1016/j.

yrtph.2019.104574.

Net S, Sempere R, Delmont A, Paluselli A, Ouddane B. Occurrence, fate, behavior and ecotoxicological state of phthalates in different environmental matrices. Environ Sci Technol. 2015; 49(7):4019-4035. doi:10.1021/es505233b.

Liu H, Cui K, Zeng F, Chen L, Cheng Y, Li H, Li S, Zhou X, Zhu F, Ouyang G, Luan T, Zeng Z. Occurrence and distribution of phthalate esters in riverine sediments from the Pearl River Delta region, South China. Mar Pollut Bull. 2014; 83(1):358-365. doi:10.1016/j.

marpolbul.2014.03.038.

Gao DW, Wen ZD. Phthalate esters in the environment: A critical review of their occurrence, biodegradation, and removal during wastewater treatment processes. Sci Total Environ. 2016; 541:986-1001. doi:10.1016/j.scitotenv.2015.09.148.

Keith L, Telliard W. ES and T special report: priority pollutants: I-a perspective view. Environ Sci Technol. 1979; 13(4):416-423. doi:10.1021/es60152a601.

Heudorf U, Mersch-Sundermann V, Angerer J. Phthalates: Toxicology and exposure. Int J Hyg Environ Health. 2007; 210(5):623-634. doi:10.1016/j.ijheh.

07.011.

Paluselli A, Aminot Y, Galgani F, Net S, Sempere R. Occurrence of phthalate acid esters (PAEs) in the northwestern Mediterranean Sea and the Rhone River. Prog Oceanography 2018; 163:221-231. doi:10.1016/j.pocean.2017.06.002ff.

Godwin AD. Plasticizers. Applied plastics engineering handbook, 2011; 487-501. doi:10.1016/b978-1-4377-3514-7.100

-5.

Wittassek M, Angerer J. Phthalates: Metabolism and exposure. Int J Androl. 2008; 31(2):131-138. doi:10.1111/j.1365-2605.2007.00837.x.

Mulder K, Knot M. PVC plastic: A history of systems development and entrenchment. Technol Soc. 2001; 23

(2):265-286. doi:10.1016/s0160-791x(01)

-6.

Gimeno P, Maggio AF, Bousquet C, Quoirez A, Civade C, Bonnet PA. Analytical method for the identification and assay of 12 phthalates in cosmetic products: Application of the ISO 12787 international standard "Cosmetics-Analytical methods-Validation criteria for analytical results using chromatographic techniques". J Chromatogr A. 2012; 1253:144-153. doi:10.1016/j.chroma.

06.090.

Bilal M, Iqbal HMN. An insight into toxicity and human-health-related adverse consequences of cosmeceuticals - A review. Sci Total Environ. 2019; 670:555-568. doi:10.1016/j.scitotenv.2019.03.261.

Koniecki D, Wang R, Moody RP, Zhu J. Phthalates in cosmetic and personal care products: Concentrations and possible dermal exposure. Environ Res. 2011; 111(3):329-336. doi:10.1016/j.envres.

01.013.

Li D, Suh S. Health risks of chemicals in consumer products: A review. Environ Int. 2019; 123:580-587. doi:10.1016/j.

envint.2018.12.033.

Geiss O, Tirendi S, Barrero-Moreno J, Kotzias D. Investigation of volatile organic compounds and phthalates present in the cabin air of used private cars. Environ Int. 2009; 35(8):1188-1195. doi:10.1016/j.envint.2009.07.016.

Schierow L, Lee MM. Congressional research service report RL34572: Phthalates in plastics and possible human health effects. 2008. Available at www.policyarchive.org/handle/10207/bitstreams/19121.pdf.

Sathyanarayana S, Karr CJ, Lozano P, Brown E, Calafat AM, Liu F, Swan SH. Baby care products: Possible sources of infant phthalates exposure. Pediatrics 2008; 121(2):e260-268. doi:10.1542/

peds.2006-3766.

Lioy PJ, Hauser R, Gennings C, Koch HM, Mirkes PE, Schwetz BA, Kortenkamp A. Assessment of phthalates/ phthalate alternatives in children’s toys and childcare articles: Review of the report including conclusions and recommendation of the chronic hazard advisory panel of the consumer product safety commission. J Expo Sci Environ Epidemiol. 2015; 25(4):343-353. doi:10.

/jes.2015.33.

Fierens T, Servaes K, Van Holderbeke M, Geerts L, De Henauw S, Sioen I, Vanermen G. Analysis of phthalates in food products and packaging materials sold on the Belgian market. Food Chem Toxicol. 2012; 50(7):2575-2583. doi:10.1016/j.fct.2012.04.029.

Petersen JH, Breindahl T. Plasticizers in total diet samples, baby food and infant formulae. Food Addit Contam. 2000; 17(2):133-141. doi:10.1080/026520300

Chou K, Wright RO. Phthalates in food and medical devices. J Med Toxicol. 2006; 2(3):126-135. doi:10.1007/bf03161027.

Jiao Y, Fu S, Ding L, Gong Q, Zhu S, Wang L, Li H. Determination of trace leaching phthalate esters in water by magnetic solid phase extraction based on magnetic multi-walled carbon nanotubes followed by GC-MS/MS. Anal Methods 2012; 4:2729-2734. doi:10.1039/

C2AY25386K.

Mousa A, Basheer C, Al‐Arfaj AR. Determination of phthalate esters in bottled water using dispersive liquid–liquid microextraction coupled with GC-MS. J Sep Sci. 2013; 36:2003-2009. doi:10.1002/jssc.201300163.

Wu PG, Pan XD, Ma BJ, Wang LY, Zhang J. Determination of phthalate esters in non-alcoholic beverages by GC-MS and optimization of the extraction conditions. Eur Food Res Technol. 2014; 238:607-612. doi:10.1007/s00217-013-2139-y.

Ye X, Kuklenyik Z, Needham LL, Calafat AM. Automated on-line column-switching HPLC-MS/MS method with peak focusing for the determination of nine environmental phenols in urine. Anal Chem. 2005; 77(16):5407-5413. doi:10.10

/ac050390d.

Leng G, Chen W, Zhang M, Huang F, Cao Q. Determination of phthalate esters in liquor samples by vortex‐assisted surfactant‐enhanced‐emulsification liquid–liquid microextraction followed by GC-MS. J Sep Sci. 2014; 37(6):684-690. doi:10.1002/jssc.201301033.

Yan Z, He M, Chen B, Gui B, Wang C, Hu B. Magnetic covalent triazine framework for rapid extraction of phthalate esters in plastic packaging materials followed by gas chromatography-flame ionization detection. J Chromatogr A. 2017; 1525:32-41. doi:10.1016/j.chroma.

10.025.

Sukree W, Sooksawat D, Kanatharana P, Thavarungkul P, Thammakhet-Buranachai C. A miniature stainless steel net dumbbell-shaped stir-bar for the extraction of phthalate esters in instant noodle and rice soup samples. J Environ Sci Health B. 2020; 55(1):60-68. doi:10.1080/03601234.

1659053.

Jiang X, Xie Y, Wan D, Zheng F, Wang J. Enrichment-free rapid detection of phthalates in Chinese liquor with electrochemical impedance spectroscopy. Sensors 2020; 20(3):901. doi:10.3390/s

Venkatesh S, Yeung CC, Sun QJ, Zhuang J, Li T, Li RKY, Roy VAL. Selective and sensitive onsite detection of phthalates in common solvents. Sensors and Actuators, B: Chemical. 2018; 259:650-657. doi:10.1016/j.snb.2017.12.107.

Group EF. Environmental fate and aquatic toxicology studies on phthalate esters. Environ Health Perspect. 1986; 65:337-340. doi:10.1289/ehp.8665337.

Rudel R, Perovich L. Endocrine disrupting chemicals in indoor and outdoor air. Atmos Environ. 2008; 43(1):170-181. doi:10.1016/j.atmosenv.2008.09.025.

Sopheak N, Sempere R, Delmont A, Paluselli A, Ouddane B. Occurrence, fate, behavior and ecotoxicological state of phthalates in different environmental matrices. Environ Sci Technol. 2015; 49(7):4019-4035. doi:10.1021/es505233b.

Tyl R. Developmental toxicity evaluation of dietary di(2-ethylhexyl)phthalate in Fischer 344 rats and CD-1 mice. Fundam Appl Toxicol. 1988; 10(3):395-412. doi:10.1016/0272-0590(88)90286-2.

Merkle J, Klimisch H, Jackh R. Developmental toxicity in rats after inhalation exposure of di-2-ethylhexylphthalate (DEHP). Toxicol Lett. 1988; 42(2):215-223. doi:10.1016/0378-4274(88)90080-x.

Field EA, Price CJ, Sleet RB, George JD, Marr MC, Myers CB, Schwetz BA, Morrissey RE. Developmental toxicity evaluation of diethyl and dimethyl phthalate in rats. Teratology 1993; 48(1):33-44. doi:10.1002/tera.1420480107

Ema M, Amano H, Ogawa Y. Characterization of the developmental toxicity of di-n-butyl phthalate in rats. Toxicology 1994; 86(3):163-174. doi:10.1016/0300-483x(94)90002-7.

Saillenfait AM, Payan JP, Fabry JP, Beydon D, Langonne I, Gallissot F, Sabate JP. Assessment of the developmental toxicity, metabolism, and placental transfer of di-n-butyl phthalate administered to pregnant rats. Toxicol Sci. 1998; 45(2):212-224. doi:10.1006/toxs.

2518.

Foster PM, Cattley RC, Mylchreest E. Effects of di-n-butyl phthalate (DBP) on male reproductive development in the rat: Implications for human risk assessment. Food Chem Toxicol. 2000; 38(1):S97-99. doi:10.1016/s0278-6915(99)00128-3.

Foster PM, Mylchreest E, Gaido KW, Sar M. Effects of phthalate esters on the developing reproductive tract of male rats. Hum Reprod Update. 2001; 7(3):231-235. doi:10.1093/humupd/7.3.231.

Ema M. Antiandrogenic effects of dibutyl phthalate and its metabolite, monobutyl phthalate, in rats. Congenit Anom. 2002; 42(4):297-308. doi:10.1111/j.1741-4520.

tb00896.x.

Barlow NJ, McIntyre BS, Foster PM. Male reproductive tract lesions at 6, 12, and 18 months of age following in utero exposure to di(n-butyl) phthalate. Toxicol Pathol. 2004; 32(1):79-90. doi:10.1080/

Lee KY, Shibutani M, Takagi H, Kato N, Takigami S, Uneyama C, Hirose M. Diverse developmental toxicity of di-n-butyl phthalate in both sexes of rat offspring after maternal exposure during the period from late gestation through lactation. Toxicology 2004; 203(1-3):221-238. doi:10.1016/j.tox.2004.06.013.

McKee RH, Pavkov KL, Trimmer GW, Keller LH, Stump DG. An assessment of the potential developmental and reproductive toxicity of di-isoheptyl phthalate in rodents. Reprod Toxicol. 2006; 21(3):241-252. doi:10.1016/j.

reprotox.2005.09.002.

Jiang J, Ma L, Yuan L, Wang X, Zhang W. Study on developmental abnormalities in hypospadiac male rats induced by maternal exposure to di-n-butyl phthalate (DBP). Toxicology 2007; 232(3):286-293. doi:10.1016/j.tox.2007.01.018.

Jiang JT, Sun WL, Jing YF, Liu SB, Ma Z, Hong Y, Ma L, Qin C, Liu Q, Stratton HJ, Xia SJ. Prenatal exposure di-n-butyl phthalate induces anorectal malformations into male rat offspring. Toxicology 2011; 290(2-3):322-326. doi:10.1016/j.tox.2011.

008.

Dobrzynska MM, Tyrkiel EJ, Pachocki KA. Developmental toxicity in mice following paternal exposure to di-n-butyl-phthalate (DBP). Biomed Environ Sci. 2011; 24(5):569-578. doi:10.3967/0895-3988.2011.05.017.

Hoshi H, Ohtsuka T. Adult rats exposed to low-doses of di-n-butyl phthalate during gestation exhibit decreased grooming behavior. Bull Environ Contam Toxicol. 2009; 83(1):62-66. doi:10.1007/s00128-009-9729-1.

Saillenfait AM, Sabate JP, Robert A, Cossec B, Roudot AC, Denis F, Burgart M. Adverse effects of diisooctyl phthalate on the male rat reproductive development following prenatal exposure. Reprod Toxicol. 2013; 42:192-202. doi:10.1016/j.

reprotox.2013.09.004.

Sun W, Ban JB, Zhang N, Zu YK, Sun WX. Perinatal exposure to di-(2-ethylhexyl)-phthalate leads to cognitive dysfunction and phospho-tau level increase in aged rats. Environ Toxicol. 2014; 29(5):596-603. doi:10.1002/

tox.21785.

Wood RK, Crowley E, Martyniuk CJ. Developmental profiles and expression of the DNA methyltransferase genes in the fathead minnow (Pimephales promelas) following exposure to di-2-ethylhexyl phthalate. Fish Physiol Biochem. 2016; 42(1):7-18. doi:10.1007/s10695-015-0112-3.

Wang Y, Yang Q, Liu W, Yu M, Zhang Z, Cui X. Di(2-ethylhexyl) phthalate exposure in utero damages Sertoli cell differentiation via disturbance of sex determination pathway in fetal and postnatal mice. Toxicol Sci. 2016; 152(1):53-61. doi:10.1093/toxsci/kfw063.

Dobrzynska MM, Tyrkiel EJ, Gajowik A. Three generation study of reproductive and developmental toxicity following exposure of pubescent F0 male mice to di-n-butyl phthalate. Mutagenesis 2017; 32(4):445-454. doi:10.1093/mutage/

gex011.

Patyna PJ, Brown RP, Davi RA, Letinski DJ, Thomas PE, Cooper KR, Parkerton TF. Hazard evaluation of diisononyl phthalate and diisodecyl phthalate in a Japanese medaka multigenerational assay. Ecotoxicol Environ Saf. 2006; 65(1):36-47. doi:10.1016/j.ecoenv.2005.05.023.

Hu X, Li W, Tian F, Wang Y, Song W, Li R, Ding X, Jin T. Study on gonadal developmental toxicity of dibutyl phthalate in male zebrafish of F1 generation. Wei Sheng Yan Jiu. 2010; 39(2):231-234.

Sun G, Liu K. Developmental toxicity and cardiac effects of butyl benzyl phthalate in zebrafish embryos. Aquat Toxicol. 2017; 192:165-170. doi:10.1016/j.aquatox.

09.020.

Jacobs HM, Sant KE, Basnet A, Williams LM, Moss JB, Timme-Laragy AR. Embryonic exposure to mono(2-ethylhexyl) phthalate (MEHP) disrupts pancreatic organogenesis in zebrafish (Danio rerio). Chemosphere 2018; 195:498-507. doi:10.1016/j.

chemosphere.2017.12.094.

Jergensen T, Cusmano D, Roy NM. Di-butyl phthalate (DBP) induces craniofacial defects during embryonic development in zebrafish. Ecotoxicology 2019; 28(8):995-1002. doi:10.1007/s10646-019-02100-7.

Pu SY, Hamid N, Ren YW, Pei DS. Effects of phthalate acid esters on zebrafish larvae: Development and skeletal morphogenesis. Chemosphere 2020; 246:125808. doi: 10.1016/j.

chemosphere.2019.125808.

Tanaka T. Reproductive and neurobehavioural toxicity study of bis(2-ethylhexyl) phthalate (DEHP) administered to mice in the diet. Food Chem Toxicol. 2002; 40(10):1499-1506. doi:10.1016/s0278-6915(02)00073-x.

Ishido M, Masuo Y, Sayato-Suzuki J, Oka S, Niki E, Morita M. Dicyclohexylphthalate causes hyperactivity in the rat concomitantly with impairment of tyrosine hydroxylase immunoreactivity. J Neurochem. 2004; 91(1):69-76. doi:10.1111/j.1471-4159.2

02696.x.

Dalsenter PR, Santana GM, Grande SW, Andrade AJ, Araújo SL. Phthalate affect the reproductive function and sexual behavior of male Wistar rats. Hum Exp Toxicol. 2006; 25(6):297-303. doi:10.

/0960327105ht624oa.

Li Y, Zhuang M, Li T, Shi N. Neurobehavioral toxicity study of dibutyl phthalate on rats following in utero and lactational exposure. J Appl Toxicol. 2009; 29(7):603-611. doi:10.1002/jat.

Min A, Liu F, Yang X, Chen M. Benzyl butyl phthalate exposure impairs learning and memory and attenuates neurotransmission and CREB phosphorylation in mice. Food Chem Toxicol. 2014; 71:81-89. doi:10.1016/j.

fct.2014.05.021.

Xu X, Yang Y, Wang R, Wang Y, Ruan Q, Lu Y. Perinatal exposure to di-(2-ethylhexyl) phthalate affects anxiety- and depression-like behaviors in mice. Chemosphere 2015; 124:22-31. doi:10.1016/j.chemosphere.2014.10.056.

Dai Y, Yang Y, Xu X, Hu Y. Effects of uterine and lactational exposure to di-(2-ethylhexyl) phthalate on spatial memory and NMDA receptor of hippocampus in mice. Horm Behav. 2015; 71:41-48. doi:10.1016/j.yhbeh.2015.03.008.

Revathy V, Chitra KC. Acute exposure to Diisononyl phthalate (DINP) influenced histopathological and behavioural modification on the freshwater fish, Oreochromis mossambicus (Peters, 1852). Int J Res. 2015; 2(4):464-477.

Wang R, Xu X, Zhu Q. Pubertal exposure to di-(2-ethylhexyl) phthalate influences social behavior and dopamine receptor D2 of adult female mice. Chemosphere 2016; 144:1771-1779. doi:10.1016/j.chemosphere.2015.10.062.

Quinnies KM, Harris EP, Snyder RW, Sumner SS, Rissman EF. Direct and transgenerational effects of low doses of perinatal di-(2-ethylhexyl) phthalate (DEHP) on social behaviors in mice. PLoS One 2017; 12(2):e0171977. doi:10.1371/

journal.pone.0171977.

Carbone S, Ponzo OJ, Gobetto N, Samaniego YA, Reynoso R, Moguilevsky JA, Cutrera RA. Effect of di(2-ethylhexyl) phthalate on the neuroendocrine regulation of reproduction in adult male rats and its relationship to anxiogenic behavior: Participation of GABAergic system. Hum Exp Toxicol. 2019; 38(1):25-35. doi:10.1177/0960327118774868.

Mahaboob BP, Radha MJ. Gestational and lactational exposition to di-n-butyl phthalate increases neurobehavioral perturbations in rats: A three generational comparative study. Toxicol Rep. 2020; 7:480-491. doi:10.1016/j.toxrep.2020.

006.

Wibe AE, Billing A, Rosenqvist G, Jenssen BM. Butyl benzyl phthalate affects shoaling behavior and bottom-dwelling behavior in threespine stickleback. Environ Res. 2002; 89(2):180-187. doi:10.1006/enrs.2002.

Kaplan LA, Nabel M, Van Cleef-Toedt K, Proffitt AR, Pylypiw HM. Impact of benzyl butyl phthalate on shoaling behavior in Fundulus heteroclitus (Mummichog) populations. Mar Environ Res. 2013; 86:70-75. doi:10.1016/j.

marenvres.2013.02.014.

Khalil SR, Elhakim YA, EL-Murr AE. Sublethal concentrations of di-n-butyl phthalate promote biochemical changes and DNA damage in juvenile Nile tilapia (Oreochromis niloticus). Jpn J Vet Res. 2016; 64(1):67-80. doi:10.14943/jjvr.

1.67.

Poopal RK, Zhang J, Zhao R, Ramesh M, Ren Z. Biochemical and behavior effects induced by diheptyl phthalate (DHpP) and diisodecyl phthalate (DIDP) exposed to zebrafish. Chemosphere 2020; 126498. doi:10.1016/j.chemosphere.2020.126498.

Whyatt RM, Liu X, Rauh VA, Calafat AM, Just AC, Hoepner L, Diaz D, Quinn J, Adibi J, Perera FP, Factor-Litvak P. Maternal prenatal urinary phthalate metabolite concentrations and child mental, psychomotor, and behavioral development at 3 years of age. Environ Health Perspect. 2012; 120(2):290-295. doi:10.1289/ehp.1103705.

Polanska K, Ligocka D, Sobala W, Hanke W. Phthalate exposure and child development: The Polish mother and child cohort study. Early Hum Dev. 2014; 90(9):477-485. doi:10.1016/j.earlhumdev.

06.006.

Lien YJ, Ku HY, Su PH, Chen SJ, Chen HY, Liao PC, Chen WJ, Wang SL. Prenatal exposure to phthalate esters and behavioral syndromes in children at 8 years of age: Taiwan maternal and infant cohort study. Environ Health Perspect. 2015; 123(1):95-100. doi:10.1289/

ehp.1307154.

Handy DE, Castro R, Loscalzo J. Epigenetic modifications: Basic mechanisms and role in cardiovascular disease. Circulation 2011; 123(19):2145-2156. doi:10.1161/CIRCULATIONAHA.110.956839.

Parks LG, Ostby JS, Lambright CR, Abbott BD, Klinefelter GR, Barlow NJ, Gray LE. The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat. Toxicol Sci. 2000; 58(2):339-349. doi:10.1093/toxsci/58.2.339.

Gray LE, Barlow NJ, Howdeshell KL, Ostby JS, Furr JR, Gray CL. Transgenerational effects of di-(2-ethylhexyl) phthalate in the male CRL:CD(SD) rat: Added value of assessing multiple offspring per litter. Toxicol Sci. 2009; 110(2):411-425. doi:10.1093/toxsci/kfp109.

Manikkam M, Guerrero-Bosagna C, Tracey R, Haque MM, Skinner MK. Transgenerational actions of environmental compounds on reproductive disease and identification of epigenetic biomarkers of ancestral exposures. PLoS One 2012; 7(2):e31901. doi:10.1371/

journal.pone.0031901.

Doyle TJ, Bowman JL, Windell VL, McLean DJ, Kim KH. Transgenerational effects of di-(2-ethylhexyl) phthalate on testicular germ cell associations and spermatogonial stem cells in mice. Biol Reprod. 2013; 88(5):112. doi:10.1095/

biolreprod.112.106104.

Kawano M, Qin XY, Yoshida M, Fukuda T, Nansai H, Hayashi Y, Nakajima T, Sone H. Peroxisome proliferator-activated receptor α mediates di-(2-ethylhexyl) phthalate transgenerational repression of ovarian Esr1 expression in female mice. Toxicol Lett. 2014; 228(3):235-240. doi:10.1016/j.toxlet.2014.04.019.

Zhang XF, Zhang T, Han Z, Liu JC, Liu YP, Ma JY, Li L, Shen W. Transgenerational inheritance of ovarian development deficiency induced by maternal diethylhexyl phthalate exposure. Reprod Fertil Dev. 2015; 27(8):1213-1221. doi:10.1071/RD14113.

Chen J, Wu S, Wen S, Shen L, Peng J, Yan C, Cao X, Zhou Y, Long C, Lin T, He D, Hua Y, Wei G. The mechanism of environmental endocrine disruptors (DEHP) induces epigenetic transgenerational inheritance of cryptorchidism. PLoS One 2015; 10(6):e0126403. doi:10.1371/

journal.pone.0126403.

Quinnies KM, Doyle TJ, Kim KH, Rissman EF. Transgenerational effects of di-(2-ethylhexyl) phthalate (DEHP) on stress hormones and behavior. Endocrinology 2015; 156(9):3077-3083. doi:10.1210/EN.2015-1326.

Somasundaram DB, Selvanesan BC, Ramachandran I, Bhaskaran RS. Lactational exposure to di-(2-ethylhexyl) phthalate impairs the ovarian and uterine function of adult offspring rat. Reprod Sci. 2016; 23(4):549-559. doi:10.1177/

Pocar P, Fiandanese N, Berrini A, Secchi C, Borromeo V. Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) promotes the transgenerational inheritance of adult-onset reproductive dysfunctions through the female germline in mice. Toxicol Appl Pharmacol. 2017; 322:113-121. doi:10.1016/j.taap.2017.03.008.

Zhou C, Gao L, Flaws JA. Exposure to an environmentally relevant phthalate mixture causes transgenerational effects on female reproduction in mice. Endocrinology 2017; 158(6):1739-1754. doi:10.1210/en.2017-00100.

Kamstra JH, Sales LB, Aleström P, Legler J. Differential DNA methylation at conserved non-genic elements and evidence for transgenerational inheritance following developmental exposure to mono(2-ethylhexyl) phthalate and 5-azacytidine in zebrafish. Epigenetics Chromatin. 2017; 10:20. doi:10.1186/s

-017-0126-4.

Rattan S, Brehm E, Gao L, Niermann S, Flaws JA. Prenatal exposure to di(2-ethylhexyl) phthalate disrupts ovarian function in a transgenerational manner in female mice. Biol Reprod. 2018; 98(1):130-145. doi:10.1093/biolre/iox

Brehm E, Rattan S, Gao L, Flaws JA. Prenatal exposure to di(2-ethylhexyl) phthalate causes long-term transgenerational effects on female reproduction in mice. Endocrinology 2018; 159(2):795-809. doi:10.1210/en.

-03004.

Hatcher KM, Willing J, Chiang C, Rattan S, Flaws JA, Mahoney MM. Exposure to di-(2-ethylhexyl) phthalate transgenerationally alters anxiety-like behavior and amygdala gene expression in adult male and female mice. Physiol Behav. 2019; 207:7-14. doi:10.1016/j.

physbeh.2019.04.018.

Wen Y, Rattan S, Flaws JA, Irudayaraj J. Multi and transgenerational epigenetic effects of di-(2-ethylhexyl) phthalate (DEHP) in liver. Toxicol Appl Pharmacol. 2020; 402:115123. doi:10.1016/j.taap.2020.115123.

Ohyama T. Effects of phthalate esters on the respiration of rat liver mitochondria. J Biochem. 1976; 79(1):153-158. doi:10.

/oxfordjournals.jbchem.a131042.

Melnick RL, Schiller CM. Mitochondrial toxicity of phthalate esters. Environ Health Perspect. 1982; 45:51-56. doi:10.1289/ehp.824551.

Melnick RL, Schiller CM. Effect of phthalate esters on energy coupling and succinate oxidation in rat liver mitochondria. Toxicology 1985; 34(1):13-27. doi:10.1016/0300-483x(85)90075-7.

Kora S, Sado M, Terada H. Effect of the plasticizer di-(2-ethylhexyl)phthalate on oxidative phosphorylation in rat liver mitochondria: Modification of the function of the adenine nucleotide translocator. J Pharmacobiodyn. 1988; 11(12):773-778. doi:10.1248/bpb1978.

773.

Chen SQ, Chen JN, Cai XH, Chen GR, Gao Y, Ge RS, Wu HS, Lin ZL, Lin J. Perinatal exposure to di-(2-ethylhexyl) phthalate leads to restricted growth and delayed lung maturation in newborn rats. J Perinat Med. 2010; 38(5):515-521. doi:10.1515/jpm.2010.083.

Chiang HC, Kuo YT, Shen CC, Lin YH, Wang SL, Tsou TC. Mono(2-ethylhexyl)phthalate accumulation disturbs energy metabolism of fat cells. Arch Toxicol. 2016; 90(3):589-601. doi:10.1007/s00204-014-1446-9.

Revathy V, Chitra KC. Di(2-ethylhexyl)phthalate-induced lipid peroxidation and associated oxidative stress in gill, liver and muscle tissues of the fish, Oreochromis mossambicus (Peters, 1852). Int J Theor Appl Sci. 2018; 10(2):1-9.

Moody L, Kougias D, Jung PM, Digan I, Hong A, Gorski A, Chen H, Juraska J, Pan YX. Perinatal phthalate and high-fat diet exposure induce sex-specific changes in adipocyte size and DNA methylation. J Nutr Biochem. 2019; 65:15-25. doi:10.1016/j.jnutbio.2018.

005.

Lee CY, Suk FM, Twu YC, Liao YJ. Long-term exposure to low-dose di-(2-ethylhexyl) phthalate impairs cholesterol metabolism in hepatic stellate cells and exacerbates liver librosis. Int J Environ Res Public Health. 2020; 17(11):3802. doi:10.3390/ijerph17113802.

Hsu JW, Nien CY, Yeh SC, Tsai FY, Chen HW, Lee TS, Chen SL, Kao YH, Tsou TC. Phthalate exposure causes browning-like effects on adipocytes in vitro and in vivo. Food Chem Toxicol. 2020; 142:111487. doi:10.1016/j.

fct.2020.111487.

Parmar D, Srivastava SP, Seth PK. Effect of di(2-ethylhexyl)phthalate (DEHP) on hepatic mixed function oxidases in different animal species. Toxicol Lett. 1988; 40(3):209-217. doi:10.1016/0378-4274(88)90043-4.

Venkata NG, Robinson JA, Cabot PJ, Davis B, Monteith GR, Roberts-Thomson SJ. Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast. Toxicol Lett. 2006; 163(3):224-234. doi:10.1016/j.toxlet.

11.001.

Zhou L, Chen H, Xu Q, Han X, Zhao Y, Song X, Zhao T, Ye L. The effect of di-2-ethylhexyl phthalate on inflammation and lipid metabolic disorder in rats. Ecotoxicol Environ Saf. 2019; 170:391-398. doi:10.1016/j.ecoenv.2018.12.009.

Fang H, Fang W, Cao H, Luo S, Cong J, Liu S, Pan F, Jia X. Di-(2-ethylhexyl)-phthalate induces apoptosis via the PPARγ/PTEN/AKT pathway in differentiated human embryonic stem cells. Food Chem Toxicol. 2019; 131:110552. doi:10.1016/j.fct.2019.

060.

Sakurai T, Miyazawa S, Hashimoto T. Effects of di-(2-ethylhexyl)phthalate administration on carbohydrate and fatty acid metabolism in rat liver. J Biochem. 1978; 83(1):313-320. doi:10.1093/

oxfordjournals.jbchem.a131906.

Osumi T, Hashimoto T. Enhancement of fatty acyl-CoA oxidizing activity in rat liver peroxisomes by di-(i-ethylhexyl)phthalate. J Biochem. 1978; 83(5):1361-1365. doi:10.1093/

oxfordjournals.jbchem.a132044.

Aitio A, Parkki M. Effect of phthalate esters on drug metabolizing enzyme activities in rat liver. Arch Int Pharmacodyn Ther. 1978; 235(2):

-195.

Ahmed RS, Price SC, Grasso P, Hinton RH. Hepatic nuclear and cytoplasmic effects following intermittent feeding of rats with di(2-ethylhexyl) phthalate. Food Chem Toxicol. 1990; 28(6):427-434. doi:10.1016/0278-6915(90)90089-6.

Eagon PK, Chandar N, Epley MJ, Elm MS, Brady EP, Rao KN. Di(2-ethylhexyl)phthalate-induced changes in liver estrogen metabolism and hyperplasia. Int J Cancer. 1994; 58(5):736-743. doi:10.1002/ijc.29105

Mocchiutti NO, Bernal CA. Effects of chronic di(2-ethylhexyl) phthalate intake on the secretion and removal rate of triglyceride-rich lipoproteins in rats. Food Chem Toxicol. 1997; 35(10-11):1017-1021. doi:10.1016/s0278-6915(97)87270-5.

Martinelli MI, Mocchiutti NO, Bernal CA. Dietary di(2-ethylhexyl)phthalate-impaired glucose metabolism in experimental animals. Hum Exp Toxicol. 2006; 25(9):531-538. doi:10.1191/

het651oa.

Kuramori C, Hase Y, Hoshikawa K, Watanabe K, Nishi T, Hishiki T, Soga T, Nashimoto A, Kabe Y, Yamaguchi Y, Watanabe H, Kataoka K, Suematsu M, Handa H. Mono-(2-ethylhexyl) phthalate targets glycogen debranching enzyme and affects glycogen metabolism in rat testis. Toxicol Sci. 2009; 109(1):143-151. doi:10.1093/toxsci/kfp041.

Pereira C, Mapuskar K, Rao CV. Chronic toxicity of diethyl phthalate in male Wistar rats - a dose-response study. Regul Toxicol Pharmacol. 2006; 45(2):169-177. doi:10.1016/j.yrtph.2006.04.006.

Zhao JF, Hsiao SH, Hsu MH, Pao KC, Kou YR, Shyue SK, Lee TS. Di-(2-ethylhexyl) phthalate accelerates atherosclerosis in apolipoprotein E-deficient mice. Arch Toxicol. 2016; 90(1):181-190. doi:10.1007/s00204-014-1377-5.

Takashima K, Ito Y, Gonzalez FJ, Nakajima T. Different mechanisms of DEHP-induced hepatocellular adenoma tumorigenesis in wild-type and Ppar alpha-null mice. J Occup Health. 2008; 50(2):169-180. doi:10.1539/joh.l7105.

Kim NY, Kim TH, Lee E, Patra N, Lee J, Shin MO, Kwack SJ, Park KL, Han SY, Kang TS, Kim SH, Lee BM, Kim HS. Functional role of phospholipase D (PLD) in di(2-ethylhexyl) phthalate-induced hepatotoxicity in Sprague-Dawley rats. J Toxicol Environ Health A. 2010; 73(21-22):1560-9. doi:10.1080/

2010.511582.

Ha M, Wei L, Guan X, Li L, Liu C. p53-dependent apoptosis contributes to di-(2-ethylhexyl) phthalate-induced hepatotoxicity. Environ Pollut. 2016; 208(Pt B):416-425. doi:10.1016/j.

envpol.2015.10.009.

Zhang YZ, Zuo YZ, Du ZH, Xia J, Zhang C, Wang H, Li XN, Li JL. Di (2-ethylhexyl) phthalate (DEHP)-induced hepatotoxicity in quails (Coturnix japonica) via triggering nuclear xenobiotic receptors and modulating cytochrome P450 systems. Food Chem Toxicol. 2018; 120:287-293. doi:10.1016/j.fct.2018.07.019.

Zhao Y, Fan JH, Luo Y, Talukder M, Li XN, Zuo YZ, Li JL. Di-(2-ethylhexyl) phthalate (DEHP)-induced hepatotoxicity in quail (Coturnix japonica) via suppression of the heat shock response. Chemosphere 2019; 228:685-693. doi:10.1016/j.

chemosphere.2019.04.172.

Preciados M, Yoo C, Roy D. Estrogenic endocrine disrupting chemicals influencing NRF1 regulated gene networks in the development of complex human brain diseases. Int J Mol Sci. 2016; 17(12):2086. doi:10.3390/

ijms17122086.

Cuenca L, Shin N, Lascarez-Lagunas LI, Martinez-Garcia M, Nadarajan S, Karthikraj R, Kannan K, Colaiacovo MP. Environmentally-relevant exposure to diethylhexyl phthalate (DEHP) alters regulation of double-strand break formation and crossover designation leading to germline dysfunction in Caenorhabditis elegans. PLoS Genet 2020; 16(1):e1008529. doi:10.1371/

journal.pgen.1008529.

Phillips BJ, James TE, Gangolli SD. Genotoxicity studies of di(2-ethylhexyl)phthalate and its metabolites in CHO cells. Mutat Res. 1982; 102(3):297-304. doi:10.1016/0165-1218(82)90139-2.

Watanabe E, Tsutsui T. Correlation of the ability of di(2-ethylhexyl)phthalate to induce cell transformation, chromosome aberrations, and peroxisome proliferation in cultured Syrian hamster embryo cells. Shigaku. 1989; 77(4):1371-1390.

Erkekoglu P, Rachidi W, Yuzugullu OG, Giray B, Favier A, Ozturk M, Hincal F. Evaluation of cytotoxicity and oxidative DNA damaging effects of di(2-ethylhexyl)-phthalate (DEHP) and mono(2-ethylhexyl)-phthalate (MEHP) on MA-10 Leydig cells and protection by selenium. Toxicol Appl Pharmacol. 2010; 248(1):52-62. doi:10.1016/

j.taap.2010.07.016.

Rosado-Berrios CA, Velez C, Zayas B. Mitochondrial permeability and toxicity of diethylhexyl and monoethylhexyl phthalates on TK6 human lymphoblasts cells. Toxicol In Vitro. 2011; 25(8):2010-2016. doi:10.1016/j.tiv.

08.001.

Mankidy R, Wiseman S, Ma H, Giesy JP. Biological impact of phthalates. Toxicol Lett. 2013; 217(1):50-58. doi:10.1016/j.toxlet.2012.11.025.

Jurewicz J, Radwan M, Sobala W, Ligocka D, Radwan P, Bochenek M, Hawuła W, Jakubowski L, Hanke W. Human urinary phthalate metabolites level and main semen parameters, sperm chromatin structure, sperm aneuploidy and reproductive hormones. Reprod Toxicol. 2013; 42:232-241. doi:10.1016/j.reprotox.2013.10.001.

Sun X, Lin Y, Huang Q, Shi J, Qiu L, Kang M, Chen Y, Fang C, Ye T, Dong S. Di(2-ethylhexyl) phthalate-induced apoptosis in rat INS-1 cells is dependent on activation of endoplasmic reticulum stress and suppression of antioxidant protection. J Cell Mol Med. 2015; 19(3):581-594. doi:10.1111/

jcmm.12409.

Tu Z, Mu X, Chen X, Geng Y, Zhang Y, Li Q, Gao R, Liu T, Wang Y, He J. Dibutyl phthalate exposure disrupts the progression of meiotic prophase I by interfering with homologous recombination in fetal mouse oocytes. Environ Pollut. 2019; 252(Pt A):388-398. doi:10.1016/j.envpol.2019.05.107.

Liu JC, Lai FN, Li L, Sun XF, Cheng SF, Ge W, Wang YF, Li L, Zhang XF, De Felici M, Dyce PW, Shen W. Di-(2-ethylhexyl) phthalate exposure impairs meiotic progression and DNA damage repair in fetal mouse oocytes in vitro. Cell Death Dis. 2017; 8(8):e2966. doi:10.1038/cddis.2017.350.

Karabulut G, Barlas N. Genotoxic, histologic, immunohistochemical, morphometric and hormonal effects of di-(2-ethylhexyl)-phthalate (DEHP) on reproductive systems in pre-pubertal male rats. Toxicol Res. 2018; 7(5):859-873. doi:10.1039/c8tx00045j.

Yang WK, Chiang LF, Tan SW and Chen PJ. Environmentally relevant concentrations of di(2-ethylhexyl)phthalate exposure alter larval growth and locomotion in medaka fish via multiple pathways. 2018; 640-641:512-522. doi:10.1016/j.scitotenv.

05.312.

Boran H, Terzi S. Bis(2-ethylhexyl) phthalate induces DNA strand breaks and gene expression alterations in larval zebrafish Danio rerio. Toxicol Ind Health. 2019; 35(8):520-529. doi:10.1177/0748233719869531.

Molino C, Filippi S, Stoppiello GA, Meschini R, Angeletti D. In vitro evaluation of cytotoxic and genotoxic effects of di-(2-ethylhexyl)-phthalate (DEHP) on European sea bass (Dicentrarchus labrax) embryonic cell line. Toxicol In Vitro. 2019; 56:118-125. doi:10.1016/j.tiv.2019.01.017.

Revathy V, Chitra KC. The cytotoxic and genotoxic effects of di-isononyl phthalate and di-(2-ethylhexyl) phthalate: An in vitro and in vivo approach on toxicological assessment. J Biosci Biotechnol. 2019; 8(1):69-79.

Zeliger HI. Exposure to lipophilic chemicals as a cause of neurological impairments, neurodevelopmental disorders and neurodegenerative diseases. Interdiscip Toxicol. 2013; 6(3):103-110. doi:10.2478/intox-2013-0018.

Shin HM, Schmidt RJ, Tancredi D, Barkoski J, Ozonoff S, Bennett DH, Hertz-Picciotto I. Prenatal exposure to phthalates and autism spectrum disorder in the MARBLES study. Environmental health: A global access science source. 2018; 17(1):85. doi:10.1186/s12940-018-0428-4.

Chopra V, Harley K, Lahiff M, Eskenazi B. Association between phthalates and attention deficit disorder and learning disability in U.S. children, 6-15 years. Environ Res. 2014; 128:64-69. doi:10.1016/j.envres.2013.10.004.

Qian X, Li J, Xu S, Wan Y, Li Y, Jiang Y, Zhaob H, Zhoub Y, Liaoa J, Liua H, Suna X, Liua W, Penga Y, Hua C, Zhangd B, Lue S, Cai Z, Xia, W. Prenatal exposure to phthalates and neurocognitive development in children at two years of age. Environ Int. 2019; 131:105023. doi:10.1016/j.envint.2019.

Zhang Q, Chen XZ, Huang X, Wang M, Wu J. The association between prenatal exposure to phthalates and cognition and neurobehavior of children-evidence from birth cohorts. Neurotoxicology 2019; 73:199-212. doi:10.1016/j.neuro.

04.007.

Li XJ, Jiang L, Chen L, Chen HS, Li X. Neurotoxicity of dibutyl phthalate in brain development following perinatal exposure: A study in rats. Environ Toxicol Pharmacol. 2013; 36(2):392-402. doi:10.1016/j.etap.2013.05.001.

Xu H, Shao X, Zhang Z, Zou Y, Chen Y, Han S, Wang S, Wu X, Yang L, Chen Z. Effects of di-n-butyl phthalate and diethyl phthalate on acetylcholinesterase activity and neurotoxicity related gene expression in embryonic zebrafish. Bull Environ Contam Toxicol. 2013; 91(6):635-639. doi:10.1007/s00128-013-1101-9.

Tseng IL, Yang YF, Yu CW, Li WH, Liao VH. Phthalates induce neurotoxicity affecting locomotor and thermotactic behaviors and AFD neurons through oxidative stress in Caenorhabditis elegans. PLoS One 2013; 8(12):e82657. doi:10.1371/journal.pone.0082657.

Smith CA, Holahan MR. Reduced hippocampal dendritic spine density and BDNF expression following acute postnatal exposure to di(2-ethylhexyl)phthalate in male long Evans rats. PLoS One 2014; 9(10):e109522. doi:10.1371/journal.pone.0109522.

Li X, Jiang L, Cheng L, Chen H. Dibutyl phthalate-induced neurotoxicity in the brain of immature and mature rat offspring. Brain Dev. 2014; 36(8):653-660. doi:10.1016/j.braindev.2013.09.002.

Ishido M, Suzuki J. Classification of phthalates based on an in vitro neurosphere assay using rat mesencephalic neural stem cells. J Toxicol Sci. 2014; 39(1):25-32. doi:10.2131/jts.39.25.

Wu Y, Li K, Zuo H, Yuan Y, Sun Y, Yang X. Primary neuronal-astrocytic co-culture platform for neurotoxicity assessment of di-(2-ethylhexyl) phthalate. J Environ Sci. 2014; 26(5):1145-1153. doi:10.1016/S1001-0742(13)60504-5.

Ma P, Liu X, Wu J, Yan B, Zhang Y, Lu Y, Wu Y, Liu C, Guo J, Nanberg E, Bornehag CG, Yang X. Cognitive deficits and anxiety induced by diisononyl phthalate in mice and the neuroprotective effects of melatonin. Sci Rep. 2015; 5:14676. doi:10.1038/srep14676.

Yan B, Guo J, Liu X, Li J, Yang X, Ma P, Wu Y. Oxidative stress mediates dibutyl phthalate induced anxiety-like behavior in Kunming mice. Environ Toxicol Pharmacol. 2016; 45:45-51. doi:10.1016/j.etap.2016.05.013.

Wojtowicz AK, Szychowski KA, Wnuk A, Kajta M. Dibutyl phthalate (DBP)-induced apoptosis and neurotoxicity are mediated via the aryl hydrocarbon receptor (AhR) but not by estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), or peroxisome proliferator-activated receptor gamma (PPARγ) in mouse cortical neurons. Neurotox Res. 2017; 31(1):77-89. doi:10.1007/s12640-016-9665-x.

Luu BE, Green SR, Childers CL, Holahan MR, Storey KB. The roles of hippocampal microRNAs in response to acute postnatal exposure to di(2-ethylhexyl) phthalate in female and male rats. Neurotoxicology 2017; 59:98-104. doi:10.1016/j.neuro.2017.02.004.

Kim BJ, Kim J, Keoboutdy V, Kwon HJ, Oh SH, Jung JY, Park IY, Paik KC. The effects of postnatal phthalate exposure on the development of auditory temporal processing in rats. Int J Pediatr Otorhinolaryngol. 2017; 97:61-65. doi:10.1016/j.ijporl.2017.03.036.

Yin N, Liang S, Liang S, Hu B, Yang R, Zhou Q, Jiang G, Faiola F. DEP and DBP induce cytotoxicity in mouse embryonic stem cells and abnormally enhance neural ectoderm development. Environ Pollut. 2018; 236:21-32. doi:10.1016/j.envpol.2018.01.035.

You M, Dong J, Fu Y, Cong Z, Fu H, Wei L, Wang Y, Wang Y, Chen J. Exposure to di-(2-ethylhexyl) phthalate during perinatal period gender-specifically impairs the dendritic growth of pyramidal neurons in rat offspring. Front Neurosci. 2018; 12:444. doi:10.3389/fnins.2018.00444.

Kassab RB, Lokman MS, Essawy EA. Neurochemical alterations following the exposure to di-n-butyl phthalate in rats. Metab Brain Dis. 2019; 34(1):235-244. doi:10.1007/s11011-018-0341-0.

Lee W, Cho JH, Lee Y, Lee S, Kim DH, Ha S, Kondo Y, Ishigami A, Chung HY, Lee J. Dibutyl phthalate impairs neural progenitor cell proliferation and hippocampal neurogenesis. Food Chem Toxicol. 2019; 129:239-248. doi:10.1016/j.fct.2019.04.040.

Lee SM, Jeon S, Jeong HJ, Kim BN, Kim Y. Dibutyl phthalate exposure during gestation and lactation in C57BL/6 mice: Maternal behavior and neurodevelopment in pups. Environ Res. 2020; 182:109025. doi:10.1016/j.

envres.2019.109025.

Xu S, Zhang H, Pao PC, Lee A, Wang J, Suen Chan Y, Manno Iii FAM, Wan Chan S, Han Cheng S, Chen X. Exposure to phthalates impaired neurodevelopment through estrogenic effects and induced DNA damage in neurons. Aquat Toxicol. 2020; 222:105469. doi:10.1016/j.

aquatox.2020.105469.

Li Y, Li X, Xie M, Cheng L, Chen H, Sun H, Jiang L. Toxicity of dibutyl phthalate in primary cultured rat hippocampal neurons and the toxicological mechanism. Nan Fang Yi Ke Da Xue Xue Bao. 2020; 40(2):225-232. Chinese. doi:10.12122/j.issn.1673-4254.2020.02.14.

Feng W, Liu Y, Ding Y, Mao G, Zhao T, Chen K, Qiu X, Xu T, Zhao X, Wu X, Yang L. Typical neurobehavioral methods and transcriptome analysis reveal the neurotoxicity and mechanisms of di(2-ethylhexyl) phthalate on pubertal male ICR mice with type 2 diabetes mellitus. Arch Toxicol. 2020; 94(4):1279-1302. doi:10.1007/s00204-020-02683-9.

Yang Q, Xie Y, Eriksson AM, Nelson BD, DePierre JW. Further evidence for the involvement of inhibition of cell proliferation and development in thymic and splenic atrophy induced by the peroxisome proliferator perfluoroctanoic acid in mice. Biochem Pharmacol. 2001; 62(8):1133-1140. doi:10.1016/s0006-2952(01)00752-3.

Jepsen KF, Abildtrup A, Larsen ST. Monophthalates promote IL-6 and IL-8 production in the human epithelial cell line A549. Toxicol In Vitro. 2004; 18(3):265-269. doi:10.1016/j.tiv.2003.

008.

Li L, Li HS, Song NN, Chen HM. The immunotoxicity of dibutyl phthalate on the macrophages in mice. Immunopharmacol Immunotoxicol. 2013; 35(2):272-281. doi:10.3109/08923973.2013.768267.

Xu H, Dong X, Zhang Z, Yang M, Wu X, Liu H, Lao Q, Li C. Assessment of immunotoxicity of dibutyl phthalate using live zebrafish embryos. Fish Shellfish Immunol. 2015; 45(2):286-292. doi:10.1016/j.fsi.2015.04.033.

Martins K, Applegate B, Hagedorn B, Kennish J, Zwollo P. Di(2-ethylhexyl) phthalate inhibits B cell proliferation and reduces the abundance of IgM-secreting cells in cultured immune tissues of the rainbow trout. Fish Shellfish Immunol. 2015; 44(1):332-341. doi:10.1016/j.fsi.

02.037.

Yirong C, Shengchen W, Jiaxin S, Shuting W, Ziwei Z. DEHP induces neutrophil extracellular traps formation and apoptosis in carp isolated from carp blood via promotion of ROS burst and autophagy. Environ Pollut. 2020; 262:114295. doi:10.1016/j.envpol.2020.

Reddy JK, Reddy MK, Usman MI, Lalwani ND, Rao MS. Comparison of hepatic peroxisome proliferative effect and its implication for hepatocarcinogenicity of phthalate esters, di(2-ethylhexyl) phthalate, and di(2-ethylhexyl) adipate with a hypolipidemic drug. Environ Health Perspect. 1986; 65:317-327. doi:10.1289/ehp.8665317.

Doull J, Cattley R, Elcombe C, Lake BG, Swenberg J, Wilkinson C, Williams G, van Gemert M. A cancer risk assessment of di(2-ethylhexyl)phthalate: application of the new U.S. EPA Risk Assessment Guidelines. Regul Toxicol Pharmacol. 1999; 29(3):327-357. doi:10.1006/rtph.

1296.

Rusyn I, Peters JM, Cunningham ML. Modes of action and species-specific effects of di-(2-ethylhexyl)phthalate in the liver. Crit Rev Toxicol. 2006; 36(5):459-479. doi:10.1080/104084

Onorato TM, Brown PW, Morris PL. Mono-(2-ethylhexyl) phthalate increases spermatocyte mitochondrial peroxiredoxin 3 and cyclooxygenase 2. J Androl. 2008; 29(3):293-303. doi:10.2164/jandrol.107.003335.

Kang JC, Jee JH, Koo JG, Keum YH, Jo SG, Park KH. Anti-oxidative status and hepatic enzymes following acute administration of diethyl phthalate in olive flounder Paralichthys olivaceus, a marine culture fish. Ecotoxicol Environ Saf. 2010; 73(6):1449-1455. doi:10.1016/j.ecoenv.2010.07.025.

Erkekoglu P, Rachidi W, Yuzugullu OG, Giray B, Ozturk M, Favier A, Hıncal F. Induction of ROS, p53, p21 in DEHP- and MEHP-exposed LNCaP cells-protection by selenium compounds. Food Chem Toxicol. 2011; 49(7):1565-1571. doi:10.1016/j.fct.2011.04.001.

Tetz LM, Cheng AA, Korte CS, Giese RW, Wang P, Harris C, Meeker JD, Loch-Caruso R. Mono-2-ethylhexyl phthalate induces oxidative stress responses in human placental cells in vitro. Toxicol Appl Pharmacol. 2013; 268(1):47-54. doi:10.1016/j.taap.2013.

020.

Ma P, Yan B, Zeng Q, Liu X, Wu Y, Jiao M, Liu C, Wu J, Yang X. Oral exposure of Kunming mice to diisononyl phthalate induces hepatic and renal tissue injury through the accumulation of ROS. Protective effect of melatonin. Food Chem Toxicol. 2014; 68:247-256. doi:10.1016/j.fct.2014.03.027.

Peng L. Mice brain tissue injury induced by di-isononyl phthalate exposure and the protective application of vitamin E. J Biochem Mol Toxicol. 2015; 29(7):311-320. doi:10.1002/jbt.21700.

Agus HH, Sumer S, Erkoc F. Toxicity and molecular effects of di-n-butyl phthalate (DBP) on CYP1A, SOD, and GPx in Cyprinus carpio (common carp). Environ Monit Assess. 2015; 187(7):423. doi:10.1007/s10661-015-4622-3.

Revathy V, Chitra KC. Effects of diisononyl phthalate on the antioxidant status in gill, liver and muscle tissues of the fish, Oreochromis mossambicus. Asian J Adv Basic Sci. 2018; 6(1):37-48.

Meruvu S, Zhang J, Choudhury M. Mono-(2-ethylhexyl) phthalate increases oxidative stress responsive miRNAs in first trimester placental cell line HTR8/SVneo. Chem Res Toxicol. 2016; 29(3):430-435. doi:10.1021/acs.

chemrestox.6b00038.

Kang J, Song J, Shen S, Li B, Yang X, Chen M. Diisononyl phthalate aggravates allergic dermatitis by activation of NF-kB. Oncotarget. 2016; 7(51):85472-85482. doi:10.18632/oncotarget.13403.

Qin W, Deng T, Cui H, Zhang Q, Liu X, Yang X, Chen M. Exposure to diisodecyl phthalate exacerbated Th2 and Th17-mediated asthma through aggravating oxidative stress and the activation of p38 MAPK. Food Chem Toxicol. 2018; 114:78-87. doi:10.1016/j.fct.2018.

028.

Zhao ZB, Ji K, Shen XY, Zhang WW, Wang R, Xu WP, Wei W. Di(2-ethylhexyl) phthalate promotes hepatic fibrosis by regulation of oxidative stress and inflammation responses in rats. Environ Toxicol Pharmacol. 2019; 68:109-119. doi:10.1016/j.etap.2019.

008.

Zhang G, Yang W, Jiang F, Zou P, Zeng Y, Ling X, Zhou Z, Cao J, Ao L. PERK regulates Nrf2/ARE antioxidant pathway against dibutyl phthalate-induced mitochondrial damage and apoptosis dependent of reactive oxygen species in mouse spermatocyte-derived cells. Toxicol Lett. 2019; 308:24-33. doi:10.1016/j.toxlet.2019.03.007.

Mondal S, Ghosh S, Bhattacharya S, Mukherjee S. Chronic dietary administration of lower levels of diethyl phthalate induces murine testicular germ cell inflammation and sperm pathologies: Involvement of oxidative stress. Chemosphere 2019; 229:443-451. doi:10.1016/j.chemosphere.2019.05.017.

Zou QY, Hong SL, Kang HY, Ke X, Wang XQ, Li J, Shen Y. Effect of di-(2-ethylhexyl) phthalate (DEHP) on allergic rhinitis. Sci Rep. 2020; 10(1):14625. doi:10.1038/s41598-020-71517-6.

Mills LJ, Chichester C. Review of evidence: Are endocrine-disrupting chemicals in the aquatic environment impacting fish populations? Sci Total Environ. 2005; 343(1-3):1-34. doi:10.10

/j.scitotenv.2004.12.070.

Al-Jandal N, Saeed T, Azad I, Al-Subiai S, Al-Zekri W, Hussain S, Al-Hasan E. Impact of endocrine disrupting compounds in sewage impacted coastal area on seabream. Ecotoxicol Environ Saf. 2018; 150:280-288. doi:10.1016/j.

ecoenv.2017.12.035.

Revathy V, Chitra KC. Di-isononyl phthalate (DINP) and di-(2-ethylhexyl)-phthalate (DEHP) disrupts endocrine functions in the freshwater fish, Oreochromis mossambicus (Peters, 1852). J Adv Sci Res. 2019; 10(1):26-31.

Frederiksen H, Skakkebaek NE, Andersson AM. Metabolism of phthalates in humans. Mol Nutrit Food Res. 2007; 51(7):899-911. doi:10.1002/mnfr.200600243.

Hoppin JA, Brock JW, Davis BJ, Baird DD. Reproducibility of urinary phthalate metabolites in first morning urine samples. Environ Health Perspect. 2002; 110(5):515-518. doi:10.1289/ehp.021

Wang B, Qin X, Xiao N, Yao Y, Duan Y, Cui X, Zhang S, Luo H, Sun H. Phthalate exposure and semen quality in infertile male population from Tianjin, China: Associations and potential mediation by reproductive hormones. Sci Total Environ. 2020; 744:140673. doi:10.1016/j.scitotenv.2020.140673.

Zhao TX, Wei YX, Wang JK, Han LD, Sun M, Wu YH, Shen LJ, Long CL, Wu SD, Wei GH. The gut-microbiota-testis axis mediated by the activation of the Nrf2 antioxidant pathway is related to prepuberal steroidogenesis disorders induced by di-(2-ethylhexyl) phthalate. Environ Sci Pollut Res Int. 2020; 27(28):35261-35271. doi:10.1007/s1135

-020-09854-2.

Henrotin JB, Feigerlova E, Robert A, Dziurla M, Burgart M, Lambert-Xolin AM, Jeandel F, Weryha G. Decrease in serum testosterone levels after short-term occupational exposure to diisononyl phthalate in male workers. Occup Environ Med. 2020; 77(4):214-222. doi:10.1136/oemed-2019-106261.

da Silva GN, Zauer Curi T, Lima Tolouei SE, Tapias Passoni M, Sari Hey GB, Marino Romano R, Martino-Andrade AJ, Dalsenter PR. Effects of diisopentyl phthalate exposure during gestation and lactation on hormone-dependent behaviours and hormone receptor expression in rats. J Neuroendocrinol. 2019; 31(12):e12816. doi:10.1111/jne.12816.

Chen H, Chen K, Qiu X, Xu H, Mao G, Zhao T, Feng W, Okeke ES, Wu X, Yang L. The reproductive toxicity and potential mechanisms of combined exposure to dibutyl phthalate and diisobutyl phthalate in male zebrafish (Danio rerio). Chemosphere 2020; 258:127238. doi:10.1016/j.chemosphere.

127238.

Mei Y, Rongshuang M, Ruizhi Z, Hongyuan H, Qiyue T, Shuhua Z. Effects of dimethyl phthalate (DMP) on serum sex hormone levels and apoptosis in C57 female mice. Int J Endocrinol Metab. 2019; 17(2):e82882. doi:10.5812/ijem.82882.

Chiang C, Lewis LR, Borkowski G, Flaws JA. Late-life consequences of short-term exposure to di(2-ethylhexyl) phthalate and diisononyl phthalate during adulthood in female mice. Reprod Toxicol. 2020; 93:28-42. doi:10.1016/j.

reprotox.2019.12.006.

Du Y, Guo N, Wang Y, Teng X, Hua X, Deng T, Yao Y, Yuan X, Li Y. Follicular fluid concentrations of phthalate metabolites are associated with altered intrafollicular reproductive hormones in women undergoing in vitro fertilization. Fertil Steril. 2019; 111(5):953-961. doi:10.1016/j.fertnstert.2019.01.021.

Bhatia H, Kumar A, Chapman JC, McLaughlin MJ. Long-term exposures to di-n-butyl phthalate inhibit body growth and impair gonad development in juvenile Murray rainbowfish (Melanotaenia fluviatilis). J Appl Toxicol. 2015; 35(7):806-816. doi:10.1002/jat.3076.

Guo Y, Yang Y, Gao Y, Wang X, Zhou B. The impact of long term exposure to phthalic acid esters on reproduction in Chinese rare minnow (Gobiocypris rarus). Environ Pollut. 2015; 203:130-136. doi:10.1016/j.envpol.2015.04.005.

Forner-Piquer I, Santangeli S, Maradonna F, Rabbito A, Piscitelli F, Habibi HR, Di Marzo V, Carnevali O. Disruption of the gonadal endocannabinoid system in zebrafish exposed to diisononyl phthalate. Environ Pollut. 2018; 241:1-8. doi:10.1016/j.envpol.2018.05.007.

Zhang X, Zhao Y, Cheng C, Li L, Xiao M, Zhang G, Lu X. Combined effects of di (2-ethylhexyl) phthalate and bisphenol A on thyroid hormone homeostasis in adolescent female rats. Environ Sci Pollut Res Int. 2020; 27(32):40882-40892. doi:10.1007/s11356-020-09949-w.

Dong J, Cong Z, You M, Fu Y, Wang Y, Wang Y, Fu H, Wei L, Chen J. Effects of perinatal di (2-ethylhexyl) phthalate exposure on thyroid function in rat offspring. Environ Toxicol Pharmacol. 2019; 67:53-60. doi:10.1016/j.

etap.2019.01.012.

Barlas N, Goktekin E, Karabulut G. Influence of in utero di-n-hexyl phthalate and di-cyclohexyl phthalate exposure on the endocrine glands and T3, T4, and TSH hormone levels of male and female rats: Postnatal outcomes. Toxicol Ind Health 2020; 36(6):399-416. doi:10.117

/0748233720931698.

Fukuoka M, Tanimoto T, Zhou Y, Kawasaki N, Tanaka A, Ikemoto I, Machida T. Mechanism of testicular atrophy induced by di-n-butyl phthalate in rats. Part 1. J Appl Toxicol. 1989; 9(4):277-283. doi:10.1002/jat.255009

Srivastava SP, Srivastava S, Saxena DK, Chandra SV, Seth PK. Testicular effects of di-n-butyl phthalate (DBP): Biochemical and histopathological alterations. Arch Toxicol. 1990; 64(2):148-152. doi:10.1007/BF0197

Barlow NJ, Foster PM. Pathogenesis of male reproductive tract lesions from gestation through adulthood following in utero exposure to di(n-butyl) phthalate. Toxicol Pathol. 2003; 31(4):397-410. doi:10.1080/01926230390202335.

Ikele CB, Mgbenka BO, Oluah NS. Histopathological effects of diethyl phthalate on Clarias gariepinus juveniles. Ani Res Int. 2011; 8(3):1431- 1438.

Shehata AS, El-Rehim Mohamed ZA, El-Haleem MRA, Samak MA. Effects of exposure to plasticizers di-(2-ethylhexyl) phthalate and trioctyltrimellitate on the histological structure of adult male albino rats’ liver. J Clin Toxicol. 2013; 3:169. doi:10.4172/2161-0495.1000169.

Revathy V, Chitra KC. Di(2-ethylhexyl)phthalate-induced histopathological changes in gill and liver of freshwater fish, Oreochromis mossambicus (Peters, 1852). Int J Adv Res. 2015; 3(9):263-270.

Chen P, Li S, Liu L, Xu N. Long-term effects of binary mixtures of 17α-ethinyl estradiol and dibutyl phthalate in a partial life-cycle test with zebrafish (Danio rerio). Environ Toxicol Chem. 2015; 34(3):518-526. doi:10.1002/

etc.2803.

Revathy V, Chitra KC. Studies on histopathological changes in the gill, liver, muscle and ovary of Oreochromis mossambicus (Peters) exposed to di-isononyl phthalate (DINP). Int J Curr Res. 2016; 8(3):28208-28214.

Santangeli S, Maradonna F, Zanarini M, Notarstefano V, Gioacchini G, Forner-Piquer I, Habibi H, Carnevali O. Effects of diisononyl phthalate on Danio rerio reproduction. Environ Pollut. 2017; 231(1):1051-1062. doi:10.1016/j.envpol.2017.08.060.

Chen H, Feng W, Chen K, Qiu X, Xu H, Mao G, Zhao T, Ding Y, Wu X. Transcriptomic analysis reveals potential mechanisms of toxicity in a combined exposure to dibutyl phthalate and diisobutyl phthalate in zebrafish (Danio rerio) ovary. Aquat Toxicol. 2019; 216:105290. doi:10.1016/j.aquatox.

105290

Kwon B, Shin H, Moon HB, Ji K, Kim KT. Effects of tris(2-butoxyethyl) phosphate exposure on endocrine systems and reproduction of zebrafish (Danio rerio). Environ Pollut. 2016; 214:568-574. doi:10.1016/j.envpol.

04.049.

Garcia-Rodriguez A, Gosalvez J, Agarwal A, Roy R, Johnston S. DNA damage and repair in human reproductive cells. Int J Mol Sci. 2019; 20(1):31. doi:10.3390/ijms20010031.

Barse AV, Chakrabarti T, Ghosh TK, Pal AK, Jadhao SB. Endocrine disruption and metabolic changes following exposure of Cyprinus carpio to diethyl phthalate. Pestic Biochem Physiol. 2007; 88(1):36-42. doi:10.1016/j.pestbp.

08.009.

Carnevali O, Tosti L, Speciale C, Peng C, Zhu Y, Maradonna F. DEHP impairs zebrafish reproduction by affecting critical factors in oogenesis. PLoS One 2010; 5(4):e10201. doi:10.1371/journal.

pone.0010201.

Wang X, Yang Y, Zhang L, Ma Y, Han J, Yang L, Zhou B. Endocrine disruption by di-(2-ethylhexyl)-phthalate in Chinese rare minnow (Gobiocypris rarus). Environ Toxicol Chem. 2013; 32(8):1846-1854. doi:10.1002/etc.2261.

Ye T, Kang M, Huang Q, Fang C, Chen Y, Liu L, Dong S. (2014). Accumulation of di(2-ethylhexyl) phthalate causes endocrine-disruptive effects in marine medaka (Oryzias melastigma) embryos. Environ Toxicol. 2014; 31(1):116-127. doi:10.1002/tox.22028.

Kim SM, Yoo JA, Baek JM, Cho KH. (2015). Diethyl phthalate exposure is associated with embryonic toxicity, fatty liver changes, and hypolipidemia via impairment of lipoprotein functions. Toxicol In Vitro. 2015; 30(1):383-393. doi:10.1016/j.tiv.2015.09.026.

Zhu Y, Hua R, Zhou Y, Li H, Quan S, Yu Y. Chronic exposure to mono-(2-ethylhexyl)-phthalate causes endocrine disruption and reproductive dysfunction in zebrafish. Environ Toxicol Chem. 2016; 35:2117-2124. doi:10.1002/etc.

Kinch CD, Kurrasch DM, Habibi HR. Adverse morphological development in embryonic zebrafish exposed to environmental concentrations of contaminants individually and in mixture. Aquat Toxicol. 2016; 175:286-298. doi:10.1016/j.aquatox.2016.03.021.

Ma YB, Jia PP, Junaid M, Yang L, Lu CJ, Pei DS. Reproductive effects linked to DNA methylation in male zebrafish chronically exposed to environmentally relevant concentrations of di-(2-ethylhexyl) phthalate. Environ Pollut. 2018; 237:1050-1061. doi:10.1016/j.

envpol.2017.11.025.

Revathy V, Chitra KC. Di-isononyl phthalate (DINP) impairs reproduction in the freshwater fish, Oreochromis mossambicus (Peters, 1852). Asian Fish Sci. 2018; 31(4):284-296.

Sajla K, Raibeemol KP, Chitra KC. Induction of ovarian toxicity in the freshwater fish, Pseudetroplus maculatus (Bloch, 1795) after sublethal exposure of dibutyl phthalate. Int J Sci Res Biol Sci. 2019; 6(5):26-38. doi:10.26438/ijsrbs/

v6i5.2638.

Sruthi M, Raibeemol KP, Chitra KC. Involvement of dibutyl phthalate (DBP) on the male reproductive toxicity in the freshwater fish, Pseudetroplus maculatus (Bloch, 1795). J Appl Aquacul. 2020; 1-25. doi:10.1080/10454438.2020.

Revathy V, Chitra KC. Role of di-(2-ethylhexyl)-phthalate on the antioxidant status in testes and ovary of the fish, Oreochromis mossambicus (Peters, 1852). Int J Pharm Biol Sci. 2019; 9(1):1186-1194. doi:10.21276/ijpbs.

9.1.152.

Baillie-Hamilton PF. Chemical toxins: A hypothesis to explain the global obesity epidemic. J Altern Complement Med. 2002; 8(2):185-192. doi:10.1089/107555

Hao C, Cheng X, Xia H, Ma X. The endocrine disruptor mono-(2-ethylhexyl) phthalate promotes adipocyte differentiation and induces obesity in mice. Biosci Rep. 2012; 32(6):619-629. doi:10.1042/BSR20120042.

Kloting N, Hesselbarth N, Gericke M, Kunath A, Biemann R, Chakaroun R, Kosacka J, Kovacs P, Kern M, Stumvoll M, Fischer B, Rolle-Kampczyk U, Feltens R, Otto W, Wissenbach DK, von Bergen M, Bluher, M. Di-(2-ethylhexyl)-phthalate (DEHP) causes impaired adipocyte function and alters serum metabolites. PLoS One 2015; 10(12):e0143190. doi:10.1371/

journal.pone.0143190.

Buerger AN, Schmidt J, Chase A, Paixao C, Patel TN, Brumback BA, Kane AS, Martyniuk CJ, Bisesi JH Jr. Examining the responses of the zebrafish (Danio rerio) gastrointestinal system to the suspected obesogen diethylhexyl phthalate. Environ Pollut. 2019; 245:1086-1094. doi:10.1016/j.

envpol.2018.11.032.

Buerger AN, Dillon DT, Schmidt J, Yang T, Zubcevic J, Martyniuk CJ, Bisesi JH. Gastrointestinal dysbiosis following diethylhexyl phthalate exposure in zebrafish (Danio rerio): Altered microbial diversity, functionality, and network connectivity. Environ Pollut. 2020; 265(Pt B):114496. doi:10.1016/j.envpol.2020.114496.

Rodriguez-Carmona Y, Cantoral A, Trejo-Valdivia B, Tellez-Rojo MM, Svensson K, Peterson KE, Meeker JD, Schnaas L, Solano M, Watkins DJ. Phthalate exposure during pregnancy and long-term weight gain in women. Environ Res. 2019; 169:26-32. doi:10.1016/j.envres.2018.10.014.

Apau J, Sefah W, Adua E. Human contact with phthalates during early life stages leads to weight gain and obesity. Cogent Chem. 2020; 6:1:1815273. doi:10.1080/23312009.2020.1815273.


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