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Phthalates, ovarian function and fertility in adulthood

Eleftheria M. Panagiotou, Venla Ojasalo, Pauliina Damdimopoulou
2021 Baillière's Best Practice & Research. Clinical Endocrinology & Metabolism  
Email addresses: Eleftheria Maria Panagiotou eleftheria.maria.panagiotou@ki.se ; 15 Pauliina Damdimopoulou pauliina.damdimopoulou@ki.se ; Venla Ojasalo 16 venla.i.ojasalo@utu.fi 17 18 J o u r n a l P r e -p r o o f ABSTRACT 19 Phthalates are a family of high-production volume industrial chemicals used in the 20 manufacture of plastics. Some phthalates are regulated as endocrine disrupting chemicals 21 (EDCs) and reproductive toxicants based on adverse effects in the male. Potential effects 22
more » ... ential effects 22 in females are less understood although exposure levels can be higher in women 23 compared to men. Here, we review the literature on the effects of phthalate exposures in 24 adulthood on ovarian function and fertility in women. Experimental studies using cell 25 cultures and rodents combined with human evidence from epidemiological studies 26 suggest that phthalates pose a hazard to ovaries. Phthalates can disrupt follicle growth 27 pattern, increase oxidative stress and cause follicle death. These effects could lead to 28 infertility, faster depletion of ovarian reserve, and earlier reproductive senescence. 29 However, more studies using more realistic exposure levels will be needed to properly 30 assess the risks in women. 31 32 fertility 35 Abbreviations: dibutylphthalate (DBP); di(2-ethylhexyl) phthalate (DEHP); 36 diethylpthalate (DEP); diisononyl phthalate (DINP); dimethylphthalate (DMP); endocrine 37 disrupting chemical (EDC); mono(2-ethylhexyl) phthalate (MEHP) 38 39 J o u r n a l P r e -p r o o f 41 1.1. Phthalate exposure and metabolism 42 43 Phthalates are a diverse group of synthetic esters of phthalic acid that vary in length and 44 branching of the alkyl side chains. Long-chain phthalates are often used as plasticizers 45 and short-chain phthalates as solvents. As plasticizers, phthalates enhance the durability 46 and flexibility of the product 1 . In flexible plastics like polyvinyl chloride (PVC), 47 phthalates can comprise up to 80% of the final product weight 1 . The shorter and more 48 volatile phthalates are widely used as solvents and carriers in a variety of personal care 49 products, including lotions, perfumes, shampoos, hair sprays and makeup 2 . Phthalates are 50 also used in soft tubing of medical devices and as excipients in medications 2 . Commonly 51 used phthalates include di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), 52 dibutylphthalate (DBP), dimethylphthalate (DMP), diethylpthalate (DEP). In plastics, 53 phthalates are not covalently bound to the structure, which means that they leach from the 54 products and end up contaminating food, water, soil, air and dust 2 . General populations 55 are exposed to phthalates and their mixtures primarily via intake of contaminated food as 56 well as by inhalation of air-borne phthalates and direct skin contact with phthalate 57 containing products 2 . 58 59 Upon uptake, phthalates are quickly metabolized in the body to a variety of biologically 60 active metabolites. Phthalates do not bioaccumulate and are excreted from the body via 61 urine, feces and breast milk 3 . Short-chain phthalates can be excreted unchanged from the 62 J o u r n a l P r e -p r o o f body, whereas long-chain phthalates are converted to a more water-soluble form for 63 excretion 3 . Phthalates are hydrolyzed to mono-alkyl phthalate esters already upon uptake 64 in the gut epithelium, and extensive continued hydrolysis and oxidation in the body lead 65 to the formation of multiple secondary metabolites 3 . For example, DEHP is first rapidly 66 hydrolyzed to mono(2-ethylhexyl) phthalate (MEHP) under the catalysis of non-specific 67 lipase enzymes. The metabolism then continues by side-chain hydrolysis and oxidation 68 catalyzed by cytochrome P450 enzymes in multiple organs resulting in the formation of 69 dozens of metabolites 3,4 . Metabolism can be affected by the exposure dose and 70 physiological factors like age, body mass index and week of pregnancy 5 . Rapid 71 metabolism and excretion make phthalate exposure assessment in humans challenging. 72 Human exposure to phthalates is often quantified by the presence of metabolites in the 73 urine 3 . However, measuring total phthalate exposure is difficult because analytical 74 methods exist for only some of the metabolites and not all breakdown products are even 75 known. In addition, multiple samples would be needed for reliable estimates 6 . 76 77 Phthalates have been found in liver, lungs and adipose tissue as well as in serum, urine, 78 ovarian follicular fluid and amniotic fluid 3,5 . The presence of phthalates in ovaries and 79 amniotic fluid means that exposure is life-long starting from germ cell development and 80 fetal life 3 . Estimated exposure levels in humans vary. For example, the daily exposure of 81 the general population to DEHP has been estimated to be between 3 -30 µg/kg based on 82 urinary excreted metabolites 7 . Women are generally more exposed to phthalates than 83 men, which is attributed to more frequent use of cosmetics and toiletry products 84 containing phthalates 8 . More specifically, significantly higher concentrations of MEP and 85 J o u r n a l P r e -p r o o f leading to higher levels of exposure. For instance, urine phthalate levels are elevated 87 among hairdressers compared to the general population and are associated with the length 88 of their exposure 10 . In this study, the mean urinary concentration of MEHP was almost 89 double in hairdressers compared to the control group (10.23, 5.63 ng/mL) and the 90 maximum measurement was ten times higher (239.70, 23.34 ng/mL). 91 92 1.2 Phthalates as endocrine disrupting chemicals 93 94 Endocrine disrupters are exogenous chemicals or their mixtures that interfere with the 95 body's normal endocrine function, leading to adverse effects on an organism and its 96 future generations. Originally, studies on endocrine disruption were mainly focused on 97 mechanisms involving the estrogen and androgen receptors and steroidogenesis 11 . It has 98 become clear over the years that multiple additional modes of action can disrupt the 99 endocrine system including changes in hormone receptor activation, inactivation or 100 expression, changes in hormone-sensitive cell signaling or the epigenome, and changes in 101 hormone function such as synthesis, distribution and clearance 12 . 102 103 Currently, DEHP, BBP, DBP and DIBP have been categorized as substances of very high 104 concern due to their endocrine disruptive and reprotoxic properties in the European 105 Union (REACH, annex XIV). These classifications rely on evidence of adverse effects on 106 male reproductive health. In a guideline three-generation reproductive toxicity study 107 using rats, DEHP caused testicular defects, shorter anogenital distance and reduced sperm 108 J o u r n a l P r e -p r o o f count 13 . In humans, exposure to phthalates during fetal development significantly 109 correlates with shorter anogenital distance in baby boys, a marker of anti-androgenic 110 effects that correlates with poorer semen quality and fertility in adult life 14 . These effects 111 are thought to depend on the ability of phthalates to disrupt steroid hormone synthesis in 112 the body, leading to reduced androgen levels. Low androgen levels during development 113 lead to disrupted masculinization of the fetus that manifests as genital tract 114 malformations, susceptibility to testicular cancer and reduced semen counts, collectively 115 defined based on associations with shorter anogenital distance in baby boys can also 126 disrupt fertility in females when tested in mice 22 . When mice were exposed in utero to an 127 epidemiologically defined phthalate mixture consisting of DBP, DBzP and DiNP, not 128 only male but also female offspring were affected. In males, shorter anogenital distance, 129 lower testis weight and reduced sperm production were observed as expected. In females, 130 the same exposure levels associated with reduced ovarian weights accompanied by 131
doi:10.1016/j.beem.2021.101552 fatcat:2qezqtbutbgvjgqjulzrnsnysi