Table 4.

Effects of PFAS on the Reproductive System.

Chemical	Exposure Window	Dose	Model/Study Population	Effects	Conclusion	Reference
PFOA	Adult exposure	0, 0.31, 1.25, 5, and 20 mg/kg/day by oral gavage for 28 days	BALB/c male mice	Damaged the seminiferous tubules Reduced testosterone and progesterone levels in the testis in a dose-dependent manner Reduced sperm quality and altered expression of 93 proteins	PFOA exposure can impair male reproductive function, possibly by disturbing testosterone levels, and CPY11A1 may be a major steroidogenic enzyme targeted by PFOA.	[19]
PFOA	Adult exposure in vitro exposure of Sertoli cells	Male mice: 0–20 mg/kg/day by oral gavage for 28 days Sertoli cells: 0–500 μM for 48 h	BALB/c male mice and Sertoli cells culture	Decreased pregnant females per male mouse, decreased litter weight Damaged blood–testis barrier Decreased levels of claudin-11, connexin-43, N-cadherin, β-catenin, and occludin in the testes	Sertoli cells appear to be target of PFOA and the disruption of the blood–testis barrier may be crucial for PFOA-induced reproductive dysfunction in mice.	[94]
PFOA	Gestational exposure	2.5 or 5 mg/kg PFOA daily by gavage during gestation	Kunming mice of Clean Grade	Decreased survival number of offspring at weaning Reduced testosterone in the male offspring Damage to testis in a dose-dependent manner Decreased number of Leydig cells	PFOA exposure during pregnancy reduces survival of offspring, damages the testis, and disrupts reproductive hormones.	[95]
PFOS	Prepubertal exposure	5 or 10 mg/kg PFOS on postnatal day 35 for 21 days	Sprague Dawley rats	Decreased testosterone levels Downregulated expression of Lhcgr, Cyp11a1, and Cyp17a1 in Leydig cells Inhibited androgen secretion in immature Leydig cells Increased apoptosis in Leydig cells	PFOS directly inhibits pubertal development of Leydig cells.	[96]
PFOA	Adult exposure	Vehicle control or PFOA at 2.5 mg/kg (for Balb/c mice) and 7.5 mg/kg (for C57Bl/6 wild type and PPARα knockout mice) by oral gavage, once daily, 5 days per week for 4 weeks starting at 21 days of age	Balb/c, C57Bl/6 wild type mice, and C57Bl/6 PPARα knockout mice	Inhibited mammary gland growth in both Balb/c and C57Bl/6 wild type mice, but not in C57Bl/6 PPARα knockout mice Delayed or absence of vaginal opening and lack of estrous cycling during the experimental period Decreased ovarian steroid hormonal synthetic enzyme levels Reduced expression of estrogen- or progesterone-induced mammary growth factors	The effects of PFOA on the ovaries mediate its ability to inhibit mammary gland development in Balb/c and C57Bl/6 mice.	[97]
PFOA	Gestational exposure	2.5, 5 or 10 mg/kg/day of PFOA by gavage from gestational day 1 until the day of euthanasia	Kunming mice	Increased numbers of resorbed embryos Reduced serum progesterone levels Decreases in transcript levels for key steroidogenic enzymes Inhibited activities of superoxide dismutase and catalase Increased generation of hydrogen peroxide and malondialdehyde Down-regulated level of Bcl-2 Up-regulated p53 and BAX proteins	PFOA exposure significantly inhibits luteal function via oxidative stress and apoptosis in pregnant mice.	[98]
PFOA	in vitro exposure of oocytes and Ex vivo exposure of fetal ovaries	in vitro oocytes: 50, 100, and 150 μM for 24 h Ex vivo fetal ovaries: 28.2 μM	CD-1- mice oocytes CD-1- mice fetal ovarian tissue	Induced oocyte apoptosis and necrosis in vitro Increased ROS Caused the blockage of GJIC in cumulus cells-oocyte complexes	The ability of PFOA to disrupt the GJIC in COCs, generate ROS in the fetal ovary, and cause apoptosis and necrosis in oocytes might account for the reported association between increasing maternal plasma concentrations of PFOA with reduced fertility in women.	[99]
PFOS, PFOA, and perfluorohexane sulfonic acid	Adult exposure	PFOS, PFOA, and perfluorohexane sulfonic acid (medians of 24.5, 4.9, and 6.6 ng/mL, respectively)	105 Danish men from the general population (median age, 19 years)	Men with high combined levels of PFOS and PFOA had a median of 6.2 million normal spermatozoa in their ejaculate in contrast to 15.5 million among men with low PFOS-PFOA	High PFAS levels were associated with fewer normal sperm. High levels of PFAS may contribute to the otherwise unexplained low semen quality often seen in young men.	[100]
PFOA, PFOS	Gestational exposure	Range of maternal serum concentrations of selected PFAS: 1.26–54.28 ng/mL	169 male offspring (19–21 years of age) from a pregnancy cohort established in Aarhus, Denmark, in 19881989–	in utero exposure to PFOA was associated with lower adjusted sperm concentration and total sperm count and with higher adjusted levels of luteinizing hormone and follicle-stimulating hormone	in utero exposure to PFOA may affect adult human male semen quality and reproductive hormone levels.	[101]
PFOA	in vitro human semen exposure	PFOA 0.25, 2.5 or 25 μg/mL alone or in combination with progesterone	Mature human sperm	Reduced capacity of human spermatozoa to penetrate synthetic mucus Increased production of reactive oxygen species Compromised progesterone-induced acrosome reaction and sperm penetration into viscous medium	PFOA exposure may impair human sperm function through inducing oxidative stress and disturbing progesterone-induced Ca2+ signaling.	[102]
Perfluorodecanoic acid, perfluorohexane sulfonic acid, perfluorononanoic acid, PFOA, PFOS, perfluorododecanoic acid, perfluoroheptanoic acid, perfluorooctanesulfonamide, and perfluoroundecanoic acid measured in serum	Adult exposure	Range of serum perfluorochemical concentration: 0–43.2229 ng/mL	Operative sample: 495 women aged 18–44 years from clinical sites in the Salt Lake City or San Francisco area, US 2007–2009 Second sample: 131 women that matched to the operative sample on age and residence within a 50-mile radius of participating clinics	Serum PFOA and perfluorononanoic acid were associated with endometriosis in the operative sample Perfluorooctane sulfonic acid and PFOA increased the odds for moderate/severe endometriosis	Select PFAS are associated with endometriosis diagnosis.	[103]
PFOA, PFOS, perfluorohexane sulfonic acid, 2-(N-ethyl-PFOSA) acetate, 2-(N-methyl-PFOSA) acetate, perfluorodecanoic acid, perfluorobutane sulfonate, perfluoroheptanoic acid, perfluorononanoic acid (PFNA), perfluorooctane sulfonamide, perfluoroundecanoic acid, and perfluorododecanoic acid measured in serum	Adult exposure	Range of serum concentratios of selected PFAS: 0.07–392 ng/mL	753 women aged 20–50 years from the National Health and Nutrition Examination Survey (2003–2006) in US	Geometric mean levels of perfluorononanoic acid, PFOA, and PFOS were higher among women reporting endometriosis and endometriosis was associated with select quartiles of PFOA, PFNA, and PFOS	PFOA, PFNA, and PFOS may be associated with an increased risk of endometriosis.	[104]
Perfluorododecanoic acid, perfluoroundecanoic acid, perfluorodecanoic acid, perfluorooctane sulfonamide, PFOS, PFOA, perfluoroheptanoic acid, perfluorohexane sulfonic acid, perfluorobutane sulfonic acid (PFBS) measured in plasma	Adult exposure	Range of plasma concentratios of selected PFAS: 0.006–138 ng/mL	157 Chinese women aged 20–45 surgically confirmed endometriosis cases and 178 seeking infertility treatment because of male reproductive dysfunction in 2014 and 2015	Plasma concentrations of PFBS were associated with an increased risk of endometriosis-related infertility	Exposure to PFBS may increase the risk of female infertility due to endometriosis.	[105]
PFOA, PFOS perfluorohexane sulfonic acid, 2-(N-ethyl-PFOSA) acetate (EPAH), 2-(N-methyl-PFOSA) acetate, perfluorodecanoic acid, perfluorobutane sulfonate, perfluoroheptanoic acid, perfluorononanoic acid (PFNA), perfluorooctane sulfonamide, perfluoroundecanoic acid, perfluorooctanesulfonic, and perfluorododecanoic acid measured in blood	Adult exposure	N/A	178 healthy, naturally cycling women, aged 25–35 years in Tromsø, Norway	PFOS blood concentrations were inversely associated with salivary concentration of estradiol and progesterone Similar, but weaker results were observed for PFOA	PFOS and perfluorooctanesulfonic acid may be associated with decreased production of estradiol and progesterone in reproductive-age women.	[106]
Perfluorohexanesulfonate (PFHxS), perfluoroheptanoic acid (PFHpA), perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluorooctyl sulfonate (PFOS), perfluorodecanoic acid (PFDeA), perfluoroundecanoic acid (PFUA), perfluorododecanoic acid (PFDoA), 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (Me–PFOSA–AcOH), 2-(N-ethylperfluorooctane sulfonamido) acetic acid (Et–PFOSA–AcOH), perfluorohexanoic acid (PFHxA), and perfluorooctane sulfonamide (PFOSA) measured in serum	Adult exposure	Range of serum concentratios of selected PFAS: 3.63–13.41 ng/mL	540 subjects aged 12–30 years from a 1992 to 2000 in Taiwan	The adjusted mean serum level of sex hormone-binding globulin decreased in association with PFOA blood concentration Follicle-stimulating hormone levels were decreased in association with PFOS in the male 1217–-year-old group and with perfluoroundecanoic acid (PFUA) in the female 1217–-year-old group	Serum concentrations of PFOA, PFOS, and PFUA were negatively associated with the serum levels of sex hormone-binding globulin, follicle-stimulating hormone, and testosterone in young Taiwanese population and these effects were the strongest in the females aged 12–17.	[107]
PFOA, PFOS measured in plasma	Gestational exposure	PFOS and PFOA levels in maternal plasma were on average 35.3 and 5.6 ng/mL, respectively	1,400 women and their infants from the Danish National Birth Cohort	PFOA levels were inversely associated with birth weight	Maternal plasma PFOA levels are inversely associated with birth weight.	[108]
PFOS, PFOA, and perfluorohexane sulfonate (PFHxS) measured in serum	Maternal exposure	Range of serum concentratios of selected PFAS: 0.1–36 ng/mL	The Maternal-Infant Research on Environmental Chemicals Study is a cohort study of 2,001 women recruited before 14 weeks of gestation in 10 cities across Canada between 2008 and 2011	PFOA and PFHxS were associated with a 11 and 9% reduction in fecundability The odds of infertility increased by 31% per one standard deviation increase of PFOA	Exposure to PFOA and PFHxS, even at lower levels than previously reported, may reduce fecundability.	[109]
PFHxS, PFOS, PFOA, PFNA, perfluorodecanoic acid (PFDA), perfluorodecane sulfonate, perfluoroundecanoic acid, perfluorododecanoic acid, perfluorotridecanoic acid, perfluorotetradecanoic acid, and perfluorohexadecanoic acid measured in maternal plasma	Maternal exposure	Range of plasma concentratios of selected PFAS: 0.01–500 ng/mL	1292 pregnant women in Shanghai, China, 2012	Maternal plasma concentrations of PFOS, PFDA, and perfluoroundecanoic acid were inversely associated with anogenital distance at birth in male offspring	Higher maternal concentrations of some PFAS during pregnancy are associated with shorter anogenital distance in male infants.	[110]
PFOA	Adult exposure and in vitro exposure of Ishikawa cells	N/A	146 exposed females aged 18–21 from the Veneto region in Italy and 1080 non-exposed controls andhuman endometrial Ishikawa cells	Dysregulation of the genetic cascade leading to embryo implantation and endometrial receptivity Molecular interference with progesterone Increased age at menarche (+164 days, p=0.006) and frequency of girls with irregular periods	PFAS have endocrine-disrupting activity on progesterone-mediated endometrial function.	[111]
PFOA and PFOS	Adult exposure nd in vitro exposure of HeLa cells	Range of serum concentratios of PFOA and PFOS: 0–156.7 ng/mL in vitro exposure: 1 µM PFOA or PFOS	212 exposed males and 171 non-exposed males controls in Veneto Region, Italy from 2017 to 2018	Reduced semen quality, testicular volume, penile length, and anogenital distance Antagonistic effect of PFOA on testosterone and androgen receptor binding	PFOA and PFOS exposure affects androgenic function and impairs reproductive outcomes in males.	[112]