Table 2 Reproductive effects of BPA, phthalates and PFAS

 - Related to early onset of puberty

▪ Earlier age of vaginal opening in female mice [17].

▪ Increased uterine and ovarian volume in young female humans [33].

 - Alter mammary gland development

▪ Larger and more abundant terminal end buds in relation to ducts, decreased apoptotic activity, slowed ductal invasion of the stroma, and increased lateral branching in mammary glands of female mice [18].

▪ Altered rates of ductal migration into the stroma, increase in the percentage of ducts, terminal ducts, terminal end buds, and alveolar buds; an increase in secretory products within the alveoli of female mice [19].

 - Associated with poorer outcome following assisted reproductive technology

▪ Lower number of oocytes retrieved, fewer mature metaphase II oocytes, fewer normally fertilized oocytes, lower serum E2 levels, and a trend for having lower blastocyst formation in women [24].

▪ Poorer ovarian response, as reflected by fewer oocytes retrieved per cycle and lower serum E2 levels; reduced oocyte maturation and lower fertilization rates in women [25].

- Role in the pathophysiology of PCOS

▪ Associated with higher levels of both testosterone and androstenedione, as well as insulin resistance, in women with PCOS [28].

▪ Additionally, higher levels of DHEA in women with PCOS in another study [29].

- Alters ovarian steroidogenesis (increase testosterone production)

▪ PCOS studies: androgen levels (seen above) [28, 29].

▪ IVF studies: E2 levels (seen above) [24, 25]

- Associated with increased risk of recurrent miscarriages

▪ Higher BPA levels in women with 3 or more consecutive 1st trimester miscarriages than in healthy woman [35].

▪ Higher urinary BPA levels correlated with a 3–9 times increased risk of recurrent miscarriages in women [36].

 -Increase reactive oxygen species

▪ MEHP induced oxidative stress by disrupting the activity and the expression of the antioxidant enzymes SOD1 and GPX; also inhibited the expression of Ccnd2, Ccne1, Cdk4, and Bcl-2, but increased Bax expression in the ovarian follicles of female mice [42].

 -Alter cell cycle regulation and apoptosis

▪ High doses of MEHP inhibited granulosa cell viability and increased apoptosis rates in the ovaries of female mice [43, 44].

 -Negatively correlated with ovarian reserve

▪ Higher levels of urinary phthalate concentrations negatively correlated with antral follicle count in infertile women [50].

 - Elevated in endometriosis

▪ Women with endometriosis had significantly higher levels of phthalate metabolites in three different studies [58,59,60].

-Alters ovarian steroidogenesis and folliculogenesis

▪ Under high concentrations of MEHP, progesterone levels were markedly increased while androstenedione, testosterone, and E2 levels were significantly decreased in female mice [44].

▪ DEHP significantly inhibited progesterone secretion in a dose-dependent manner, increased plasma prostaglandin F2-alpha levels, downregulated CYP11A, 3β-HSD, and StAR, reduced the numbers and sizes of corpora lutea, and inhibited CD31 expression of corpora lutea in female mice [45].

▪ MEHP decreased testosterone, estrone, and E2 levels by downregulating mRNA levels of the enzymes: 17alpha-hydroxylase-17,20-desmolase, 17beta-hydroxysteroid dehydrogenase, and aromatase in female mice [46].

 -Alters mammary gland development

▪ Relationship between PFOA exposure and mammary gland development in female mice [64, 65].

 -Delays puberty

▪ Delay in vaginal opening female mice [66]

 -Alters ovarian steroidogenesis

▪ Decrease in ER-α and ER-β expression in the rat ovary [67]

▪ Decrease in serum E2 levels in female rats [67]

 -Alters reproductive hormone levels

▪ Serum POFA, PFOS and PFDA levels were negatively associated with serum levels of SHBG, FSH and testosterone in female humans [74].

▪ Total testosterone concentrations were higher in daughters with prenatal exposure to PFOS or PFOA in female humans [75].

 -Increased rates of infertility

▪ Women with higher serum PFOA levels [68] and higher PFNA levels [70] had higher rates of subfecundity

▪ Women with higher serum PFOA levels had longer time to achieve a pregnancy [68]

-Menstrual irregularities

▪ Women with the highest PFOA exposure had increased rates of menstrual cycle irregularities [68].

-Association with miscarriage risk

▪ No association between serum PFOA or serum PFOS levels with miscarriage rate in women [76].

▪ Little evidence for an association between serum levels of PFOA and miscarriage rate in women [77].