Other male reproductive disorders related to phthalate exposure include dysfunctions of puberty. In vitro studies demonstrated that DEHP exposure at 40, 80 and 160 μM and dibutyl phthalate (DBP) exposure at 10 and 100 mg/L caused the apoptosis of TM3 Leydig cells and Sertoli cells of Male Sprague-Dawley rats, respectively 72,73. Estradiol and progesterone are essential hormones for postnatal female reproductive system development and to enable ovarian and menstrual cycle, pregnancy, and labor. In this review, we attempted to present an overview of the current knowledge concerning the phthalates’ effect on reproductive health at multiple levels. The aim of this review was to compile the evidence concerning the association between phthalates and reproductive diseases, phthalates-induced reproductive disorders, and their possible endocrine and intracellular mechanisms. Di-n-butyl phthalate (DnBP) is classified as an endocrine disruptor, negatively impacting testosterone levels in human males.
FT, BAT, and FAI were calculated based on hormone concentrations and serum albumin levels. NHANES laboratories used spot urine samples to assess phthalate metabolite levels. However, the health effects of these substitutes have not been comprehensively studied, and in fact, DEHTP and DINCH metabolites were measured for the first time in the National Health and Nutrition Examination Survey (NHANES) in 2015–2016 (26).
The next chapter is focused on the primary mechanism of phthalate toxicity, physical and chemical properties of phthalates, and the definition of phthalate exposure sources. Testosterone and dihydrotestosterone are leading male masculinization hormones. The HPG axis regulates the levels of reproductive hormones via a positive and negative feedback loop. This review integrates the results from in silico, in vitro, in vivo studies, and epidemiological studies to show the complexity of phthalates’ effects on reproduction. One of the causes of current reproductive disorders could be environmental chemicals, such as phthalates .
Another female reproductive disorder related to phthalate exposure is a dysfunction of pregnancy. A Chinese epidemiological study involving 208 girls aged 6–14 reported the negative association between the urinary levels of MEHP, MEHHP, MEOHP and both breast development and the initiation of the menstrual cycle . Other female reproductive disorders related to phthalate exposure are dysfunctions of puberty. These studies observed phthalates’ effects on ovarian function in female rats and mice.
Altered reproductive health can be influenced by phthalates’ impact on the hormonal system. Higher levels of estradiol stimulate cell proliferation and growth, leading to the onset of hormone-dependent types of cancer, such as ovarian, uterine, and cervical cancers 169,170. In addition, a US study recruited 3003 women aged 25–85, most of whom were non-Hispanic white, whereby 20 of them were diagnosed with ovarian cancer. This study reported significantly higher urinary levels of MBP and lower levels of MEHP in women with leiomyoma . This study showed that the urinary levels of MECPP were higher in women with leiomyoma than in control subjects .
NF-κB creates a group of transcription factors that are involved in various biological processes, including immune response, inflammation, cell growth, survival, and development . The membrane progesterone receptor regulates oocyte maturation, labor, and sperm motility and reproductive organs cancer onset . The main steroid effect on the cells is mediated by genomic action . SHBG levels elevate when testosterone decreases, and when estradiol increases .
To our knowledge, there is lack of studies showing the direct effect of phthalate occupational exposure on testicular cancer. Prostate gland development is defined by their cell proliferation differentiation and apoptosis, which in turn depend on the testosterone exposure and testosterone/estradiol ratio. Furthermore, a Chinese epidemiological study involving 222 boys at the age of 6–14 years, reported the negative association between the urinary levels of MnBP and both, pubertal onset and a growth of pubic hair .
Phthalates, like hormones, exert their physiological effects in low doses rather than in high doses. These chemicals interact with each other via different mechanisms, which can lead to synergistic, additive, or antagonistic toxic health effects 68,69. They can alter the development and function of the hormone-dependent structures of the reproductive system . Steroids, but also some peptide hormones and other factors, regulate cell proliferation and apoptosis (see Table 1). These intracellular pathways can mediate steroid hormones action on cell proliferation (cellular multiplication, which leads to the growth of cell population) and of apoptosis (genetically programmed cell death). Moreover, sex steroids induce cell proliferation in the non-reproductive tissue, such as the bladder , precursors of myotubes , or neural stem cells .
However, the direct effect of phthalate exposure on puberty onset in different ethnicity is not clear yet. For example, levels of phthalates in indoor dust samples were lowest in the samples from North America (500.02 μg/g), next from Europe (580.12 μg/g) and the highest concentrations were from Asia (945.45 μg/g) . We hypothesize that the conflicting results in the associations between phthalate exposure and the onset of puberty are likely attributed to ethnicity. In the study by Mieritz et al. , they did not observe significant correlations between phthalate metabolites in the urine samples of 555 boys at the age of 16–20 years. Whether it is the acceleration or delay of puberty onset, it depends on the timing of phthalate exposure, on their concentration, and other factors . Phthalates affect the male reproductive system not only in utero, but they play a role in male postnatal sexual development and puberty.

Gender: Female

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