Review
Reproductive toxic potential of phthalate compounds – State of art review

https://doi.org/10.1016/j.phrs.2021.105536Get rights and content

Highlights

  • Phthalates exhibit reproductive toxicity in male and femalereproductive organs.

  • Phthalates express embryonic toxicity.

  • Phthalates induce oxidative stress in male and female reproductive organs.

  • Phthalates induce apoptosis in testicular cells.

  • Phthalates cause DNA damage.

Abstract

Phthalates are pervasive compounds, and due to the ubiquitous usage of phthalates, humans or even children are widely exposed to them. Since phthalates are not chemically bound to the plastic matrix, they can easily leach out to contaminate the peripheral environment. Various animal and human studies have raised vital health concern including developmental and reproductive toxicity of phthalate exposure. The present review is based upon the available literature on phthalates with respect to their reproductive toxic potential. Common reproductive effects such as declined fertility, reduced testis weight, variations in accessory sex organs and several female reproductive disorders appeared to be largely associated with the transitional phthalates. Among the higher molecular weight phthalates (≥ C7), di-isononyl phthalate (DINP) produces some minor effects on development of male reproductive tract and among low molecular weight phthalates (≤C3), di-methyl (DMP) and di-isobutyl (DIBP) phthalate produce some adverse effects on male reproductive system. Whereas transitional phthalates such as di-butyl phthalate, benzyl butyl phthalate, and di-(2-ethylhexyl) phthalate have shown adverse effects on female reproductive system. Owing to these, non-toxic alternatives to phthalates may be developed and use of phthalates could be rationalized as an important issue where human reproduction system is involved. Though, more epidemiological studies are needed to substantiate the reported findings on phthalates.

Introduction

Humans are exposed to certain persistent environmental chemicals, pesticides, heavy metals, solvents especially organic solvents, synthetic chemicals, plasticizers, illicit drugs, tobacco smoking/chewing, drinking alcohol etc. Some of these are reported to have reproductive toxic potential for both the sexes which might depend upon the dose, duration, and time of exposure to the toxicants as well as host factors such as age, sex, immunity, heredity etc., including their role in reproductive toxicity. Phthalates are just one of the many classes of chemicals that have been reported to have estrogenic or anti-androgenic properties. The approximate consumption of phthalates in the year 2017 was found to be ~ 65% of the world plasticizer consumption, which is expected to be ~ 60% of world’s consumption by the year 2022. This might be due to rapid consumption growth for non-phthalate plasticizers in recent years [1]. About three million metric tons of phthalates are produced every year, worldwide [2], [3]. Since phthalates are not chemically bound to the plastic matrix, they can easily leach out from phthalate containing products to contaminate the environment [4]. Many sustained or controlled releases drugs (enteric coated tablets) contain cellulose acetate phthalate (CAP), dimethyl phthalate (DMP), dibutyl phthalate (DBP), diethyl phthalate (DEP) and polyvinyl acetate phthalate (PVAP) [2], [5], [6]. Food and drug administration (FDA) has approved these compounds as excipients with specified amounts for each formulation and route of entry [2], [6].

Bioaccumulation of phthalates can occur in medicinal and food plants due to growing of these plants in phthalate contaminated waste water [7]. Young children suck and chew the toys as well as teether containing phthalates, so that they can extract and ingest some quantities of phthalates while chewing these materials. Di-isononyl phthalate (DINP) may be risky for those young children who frequently kept toys (plasticized with DINP) for ~75 min/day or more in their mouth [8]. Based on the available information on rodents and some from human studies, there are health concerns including developmental and reproductive toxicity in human with regard to exposure to phthalates.

It is known that phthalate esters generally consist of a di-ester structure having benzenedicarboxylic acid head group linked to two ester side chains [9]. As shown in Table 1, the phthalate esters panel HPV testing group has categorized three types of phthalates: i.e. low molecular weight phthalates, transitional phthalates and high molecular weight phthalates. Low molecular weight phthalates were defined as those produced from alcohols with straight-chain carbon backbones of ≤C3 [i.e. di-methyl phthalate (DMP), diethyl phthalate (DEP), di-alkyl phthalate (DAP), di-methylethyl phthalate (DMEP), di-isobutyl phthalate (DIBP) etc]. High molecular weight phthalates were defined as those produced from alcohols with straight-chain carbon backbones of ≥C7 or ring structure [i.e. di-isononyl phthalate (DINP), di-nonyl phthalate (DNP), di-isodocyl phthalate (DIDP) etc.]. Transitional phthalates were defined as those are produced from alcohols with straight-chain carbon backbones of C4–6 [i.e. dibutyl phthalate (DBP), benzyl butyl phthalate (BBP) and di-(2-ethylhexyl) phthalate (DEHP) etc.]. Low molecular weight phthalates such as DEP are used as a solvent and fixatives in fragrances; DMP in hair sprays to avoid stiffness of hairs, while the high molecular weight phthalates are used as plasticizers. The transitional phthalates such as DBP are used as a plasticizer in nail polishes to reduce cracking and making them less brittle [10]. They are also used as a solvent [11]. Owing to their day-to-day widespread use, application and ubiquitous nature, the present review is written with the view to look the reproductive toxic potential of phthalates. Thus, this review provides literature survey on phthalate structures, clinical and experimental studies on male and female toxicity, and oxidative stress, including mechanism of phthalate action in both male and female reproductive systems.

Section snippets

Data collection

The literature was collected through examining various data resources such as PubMed, Google, Toxnet, and through books and journals pertaining to phthalate exposure and reproductive health. In this review, we attempted to analyse the reproductive toxicity data of phthalates in adults, in utero-treated and developing animals and probable mechanism behind the reproductive impairments and possible implication of exposure to phthalates and human reproduction. This review is divided into different

Phthalate exposure and male reproduction

The effect of any compound on male reproduction can be assessed by determining the adverse effects of compound of interest on the male reproductive system, accessory organs, hormonal balance, time-to-pregnancy, pregnancy outcomes etc. Generally, effects like death, structural malformations or reduced weight of the foetuses are markers of developmental toxicity. While impairment in the reproducing capacity of in utero treated animals or the mature animals denote reproductive toxicity [12].

Clinical studies on male reproduction

There are several clinical reports which indicated that some of the phthalates have adverse effects on human male reproduction, but the data are sparse and inconsistent as human are exposed to number of other chemical and physical factors and some of them might be associated with adverse effect on reproduction. Duty et al. [34] studied whether environmental levels of phthalates are associated with altered semen quality in humans and found a dose-response relation between mono-butyl phthalate,

Phthalate exposure and female reproduction

Considerable toxicity data of phthalates on male reproduction are available as compared to female. Thus, it is generally considered that female reproduction is less sensitive to phthalates than male; however, some studies have shown that some phthalates may also have a significant effect on female reproduction. McLachlan et al. [40] reported that human development could also be feminized by exposure to estrogenic chemicals. Estrogen is the key hormone in the initiation (puberty) and the end

In utero exposure to phthalates and pregnancy outcome

Several reports indicate that in utero exposure to phthalate compounds had adverse effect on pregnancy outcome. Available experimental studies indicated that in utero exposure to phthalates led to various developmental and reproductive impairments in the offsprings. Pocar et al. [48] examined the effects of DEHP exposure in mice throughout pregnancy and lactation on the development and function of the pituitary-gonadal axis in male and female offsprings. They stated that, in maternally exposed

Clinical studies on female reproduction

A few reports claim detectable level of certain phthalates or their metabolites in the amniotic fluid (AF) indicating possible fetal exposure to these compounds. Silva et al. [55] found considerable amount of monoethyl phthalate (MEP), MBP, and MEHP in human AF, suggesting their presence in the human fetal environment in the second trimester early stages when reproductive differentiation takes place. Later, Wittassek et al. [56] collected AF and corresponding maternal urine (MU) samples, and

Embryonic toxicity

A single intraperitoneal injection (0.6 ml/kg) of di-methoxyethyl phthalate (DMEP) was given to rats during gestation. In phthalate treated rats, embryopathy was manifested by 12–79% of fetal deaths and fetal resorptions. Fetotoxicity was expressed by a significant reduction in fetal weights. DMEP caused a congenital malformation of the brain i.e. hydrocephalus interna [71]. Shiota et al. [72] treated pregnant mice with DEHP and DBP in food GD0-parturition. They observed increased resorption

Phthalate induced testicular dysgenesis and oxidative stress

Hormonally active environmental chemicals/compounds generally target the endocrine system which leads to reproductive anomalies [77]. An increase in these environmental contaminants causes disturbances in the pro-oxidant/antioxidant balance of testicular cells leading to impairment of testicular functions thereby activating apoptosis [78]. Physiological levels of reactive oxygen species (ROS) and apoptosis are necessary for the normal functioning of the testes and ovaries, but an imbalance may

Mechanism of phthalate toxicity

Definite understanding of mechanism of toxicity of phthalate is not fully known. However, several pathways are involved to induce toxicity by the phthalates. Some of the phthalates work as endocrine disruptors and are thought to be anti-androgenic. Under in vitro condition, phthalates are not androgen receptor (AR) antagonists directly at concentrations of up to 10 μM, so phthalates and their metabolites do not bind to the AR [91]. Endocrine disruptors (EDs) also act by altering the function of

Future directions and conclusions

The available studies indicate that phthalates (especially the transitional phthalates) interfere with the normal spermatogenesis leading to testicular atrophy, oxidative stress and DNA damage. They also disrupt the steroidogenic pathways leading to reduced testosterone synthesis and Insl-3 production by the fetal leydig cells which is likely to cause cryptorchidism. The data available indicate the need for the detailed experimental studies on various phthalate compounds on female reproduction,

Acknowledgments

Financial assistance provided by Council of Scientific and Industrial Research (CSIR) is duly acknowledged by Dr. Sapna Sedha. The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding this work through research group no. RG-1441-413. This study received financial support from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2021R1A5A6002853).

References (126)

  • A.M. Saillenfait et al.

    Developmental toxic effects of diisobutyl phthalate, the methyl-branched analogue of di-n-butylphthalate administration by gavage to rats

    Toxicol. Lett.

    (2006)
  • A.M. Saillenfait et al.

    Di-isobutyl phthalate impairs the androgen-dependent reproductive development of the male rat

    Reprod. Toxicol.

    (2008)
  • Y. Pan et al.

    Association between phthalate metabolites and biomarkers of reproductive function in 1066 Chinese men of reproductive age

    J. Hazard. Mater.

    (2015)
  • Y. Wang et al.

    Semen phthalate metabolites, semen quality parameters and serum reproductive hormones: a cross-sectional study in China

    Environ. Poll.

    (2016)
  • J.A. McLachlan et al.

    Endocrine disrupters and female reproductive health

    Best. Pract. Res. Clin. Endocrinol. Metab.

    (2006)
  • B.J. Davis et al.

    Di-(2-ethylhexyl) phthalate suppresses estradiol and ovulation in cycling rats

    Toxicol. Appl. Pharmacol.

    (1994)
  • M.T. Guerra et al.

    Reproductive development and function of female rats exposed to di-eta-butyl-phthalate (DBP) in utero and during lactation

    Reprod. Toxicol.

    (2010)
  • K.Y. Lee et al.

    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)
  • M. Wittassek et al.

    Fetal exposure to phthalates – a pilot study

    Int. J. Hyg. Environ. Health

    (2009)
  • Y. Zhang et al.

    Phthalate levels and low birth weight: a nested case-control study of Chinese new-borns

    J. Pediatr.

    (2009)
  • S.H. Kim et al.

    Increased plasma levels of phthalate esters in women with advanced-stage endometriosis: a prospective case-control study

    Fertil. Steril.

    (2011)
  • B.S. Reddy et al.

    High plasma concentrations of polychlorinated biphenyls and phthalate esters in women with endometriosis: a prospective case control study

    Fertil. Steril.

    (2006)
  • H. Itoh et al.

    Urinary phthalate monoesters and endometriosis in infertile Japanese women

    Sci. Total Environ.

    (2009)
  • E. Durmaz et al.

    Urinary phthalate metabolite concentrations in girls with premature thelarche

    Environ. Toxicol. Pharmacol.

    (2018)
  • J.P. Lomenick et al.

    Phthalate exposure and precocious puberty in females

    J. Pediatr

    (2010)
  • K. Shiota et al.

    Embryotoxic effects of di-2-ethylhexyl phthalate (DEHP) in mice

    Environ. Res.

    (1980)
  • E. Makoto et al.

    Teratogenic evaluation of butyl benzyl phthalate in rats by gastric intubation

    Toxicol. Lett.

    (1992)
  • K.W. Seo et al.

    Comparison of oxidative stress

    Chem. Toxicol.

    (2004)
  • V.S. Wilson et al.

    Phthalate ester-induced gubernacular lesions are associated with reduced insl3 gene expression in the fetal rat testis

    Toxicol. Lett.

    (2004)
  • J. Borch et al.

    Early testicular effects in rats perinatally exposed to DEHP in combination with DEHA-apoptosis assessment and immunohistochemical studies

    Reprod. Toxicol.

    (2005)
  • T. Nagao et al.

    Effect of butyl benzyl phthalate in Sprague-Dawley rats after gavage administration: a two-generation reproductive study

    Reprod. Toxicol.

    (2000)
  • E. Mylchreest et al.

    Foetal testosterone insufficiency and abnormal proliferation of Leydig cells and gonocytes in rats exposed to di(n-butyl) phthalate

    Reprod. Toxicol.

    (2002)
  • Y.C. Hong et al.

    Community level exposure to chemicals and oxidative stress in adult population

    Toxicol. Lett.

    (2009)
  • K. Ji et al.

    Influence of a five-day vegetarian diet on urinary levels of antibiotics and phthalate metabolites: a pilot study with “temple stay” participants

    Environ. Res.

    (2010)
  • I.H.S. Markit , Plasticizers: Chemical Economics Handbook, May , 2018....
  • H. Bahadar et al.

    Consumption of phthalates coated pharmaceutical tablets: an unnoticed threat

    Int. J. Pharmacol.

    (2014)
  • T. Schettler

    Human exposure to phthalates via consumer products

    Int. J. Androl.

    (2006)
  • C.E. Talsness et al.

    Components of plastic: experimental studies in animals and relevance for human health

    Philos. Trans. R. Soc. Lond. B Biol. Sci.

    (2009)
  • R. Hauser et al.

    Medications as a source of human exposure to phthalates

    Environ. Health Perspect.

    (2004)
  • FDA- Food and Drug Administration , Inactive ingredient search for approved drug products: Frequently asked questions,...
  • S. Saeidnia et al.

    Are medicinal plants polluted with phthalates?

    DARU J. Pharm. Sci.

    (2013)
  • K.T. Bogen et al.

    Report to the US consumer product safety commission by the chronic hazard advisory panel on di-isononyl phthalate

    Bethesda

    (2001)
  • NICNAS. Existing chemical hazards assessment report. Di-isoundecyl phthalate , 2008....
  • Phthalate Esters Panel HPV Testing Group, High production volume (HPV) chemical challenge programme test plan for the...
  • Phthalate Hazard Compendium, A summary of physicochemical and human health hazard data for 24 ortho-phthalate...
  • NTP-CERHR, Monograph on the potential human reproductive and developmental effects of di-isononyl phthalate (DINP),...
  • L.E. Gray et al.

    Perinatal exposure to the phthalates DEHP, BBP and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat

    Toxicol. Sci.

    (2000)
  • K. Howdeshell et al.

    A mixture of five phthalate esters inhibits fetal testicular testosterone production in the Sprague-Dawley rats in a cumulative, dose additive manner

    Toxicol. Sci.

    (2008)
  • NTP-CERHR , Monograph on the potential human reproductive and developmental effects of di-hexyl phthalate (DHP), 2003b....
  • M.R. Moore

    Oncogenicity study in mice with di(isononyl)phthalate including ancillary hepatocellular proliferation and biochemical analyses. Covance Laboratories 144 Inc., Vienna, VA 22182. For Aristech Chemical Corporation, Pittsburgh, PA 15230. January 29

    Covance

    (1998)
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