ReviewReproductive toxic potential of phthalate compounds – State of art review
Graphical Abstract
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).
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