ReviewFetal origin of endocrine dysfunction in the adult: The phthalate model
Graphical abstract
Highlights
► Phthalate plasticizers are found ubiquitously in the environment and human fluids. ► The effects of DEHP are more severe and long lasting when exposures occur during fetal development. ► Early in life exposure to DEHP affects male and female offspring reproductive function. ► Exposure to DEHP in utero decreases aldosterone levels and blood pressure in the male offspring.
Introduction
Phthalate esters are used in industry as plasticizers to add softness and flexibility to polyvinyl chloride (PVC) plastics. Phthalate-free PVC is white and rigid, but with the addition of phthalates it can be molded and used for a wide variety of products, including personal care products, toys, food wrappings, medical devices, lubricants, waxes, insecticides, and building and household products among many others [1], [2]. Interestingly, medical devices have been identified as a potential risk to young children due to their high content of phthalates, and account for some of the highest exposures [3], [4]. Studies measuring phthalate exposure in neonatal medical intensive care units found levels as high as 50 times greater than those in children between the ages of 6 and 10 years old [5], [6], [7]. Di-(2-ethylhexyl) phthalate (DEHP) is the most commonly used phthalate in industry, with three million metric tons produced each year [8]. In some instances, DEHP can account for 40% of the total weight of the product [9]. Because DEHP is not covalently bound to the PVC polymer, it leaches into the environment and comes into contact with humans mainly through dermal exposure [10], oral ingestion [9], [11], and inhalation [12], [13]. In humans, maternal exposure to phthalates [14], [15], [16], [17] provides the first source of fetal exposure, and has been identified amniotic fluid [18], umbilical cord blood [16], and other bodily fluids [19]. This exposure to phthalates continues after birth through breast feeding [20], [21], [22], baby and infant food sources [11], [23], [24], and contact to the environment [2]. These abundant man-made sources of phthalates result in human exposure estimated at 1.7–52.1 μg/kg/day [4], [25], [26], [27], and under specific circumstances, infants can be exposed to up to 3 times as much [1]. This is a public health concern since exposure to DEHP in rodents was found to be an endocrine disruptor, and in humans there are correlations between phthalate exposure and decreased anogenital distance [17], reduced testosterone levels [28], and poor semen quality [29], [30], [31]. These clinical findings, together with cryptorchidism, hypospadias, and testicular cancer [32], were grouped under the term testicular dysgenesis syndrome (TDS), which is thought to originate from an insult to Sertoli or Leydig cell function during development [33], [34]. This has led to a focus on the possible involvement of phthalates in TDS [35], in agreement with the reported increase in cryptorchidism, hypospadias [36], [37], [38], [39], decreased semen quality [40], [41], [42], and increased testicular cancer [35]. In the female, DEHP also targets the reproductive system, but data on the mechanisms have lagged compared to the male. New data from studies of female offspring exposed in utero to DEHP is suggesting sex-specific effects of phthalates [43], and that DEHP has a multiorgan effect that depends on the time of exposure.
We will review herein the data on the long-term effects of in utero exposure to DEHP in the male and female offspring.
Section snippets
Steroidogenesis
Systemic steroid hormones are primarily formed by the gonads, adrenal glands, and during in utero development by the placenta. The brain [44], [45], [46] and heart [47], [48], [49] have also been identified as steroid-producing tissues forming limited amounts of steroid hormones mainly for local needs.
Cholesterol is the building block of steroid hormone biosynthesis and the import of cholesterol into the mitochondria is the rate-limiting step of steroidogenesis (Fig. 1) [50], [51]. This process
Testes
During early sexual development in the mouse, male and female gonads are indistinguishable and dependent on the expression of the sex-determining region of the Y chromosome (SRY) to commit to male phenotype. The initial commitment of few embryonic stem cells to become primordial germ cells occurs similarly in both sexes around GD7 [56], followed by their migration into the genital ridge between GD9 and 10.5, where they become residents in the undifferentiated gonad [57]. SRY expression results
Pharmacokinetics
DEHP is a high molecular weight compound that is first hydrolyzed by pancreatic lipases, liver esterases, and nonspecific esterases in the blood [77], [78], [79]. Further degradation produces more than 15 short branch derivatives [80], [81] (for a review on phthalate metabolism refer to Frederiksen et al. [11]). Mono(2-ethylhexyl) phthalate (MEHP) is formed after the first hydrolysis of DEHP, and is ten-times more potent than DEHP in vitro [82], [83]. In humans, MEHP is excreted in the urine
Conclusions
In utero DEHP exposure results in long-term effects in both male and the female offspring. The evidence gathered so far suggest that DEHP has the ability to target multiple tissues, particularly steroid synthesizing, in a manner depending on the window of exposure. In addition to studying the endocrine disrupting effects of DEHP, the in utero exposure model suggested the existence of an adrenal-testicular regulatory axis of androgen formation.
Competing interest
The authors declare that they have no competing interest.
Acknowledgments
Supported by a grant MOP-111131 from the Canadian Institutes of Health Research (CIHR) and a Canada Research Chair in Biochemical Pharmacology (to V.P.). The Research Institute of McGill University Health Centre is supported in part by a center grant from Fonds de la Recherche Quebec – Santé.
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