Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000072.xml
Download PDF
Semin Reprod Med 2024; 42(04): 288-301
DOI: 10.1055/s-0044-1801363
DOI: 10.1055/s-0044-1801363
Review Article
PFAS Exposure and Male Reproductive Health: Implications for Sperm Epigenetics
Funding This work was supported by the Center for Urban Responses to Environmental Stressors CURES P30 ES020957 and P30 ES036084 (M.C.P. and J.R.P.) and R01ES035692 (M.C.P.); and Robert J. Sokol, MD Endowed Chair of Molecular Obstetrics and Gynecology (J.R.P.).
Abstract
Per- and polyfluoroalkyl substances (PFASs) are persistent environmental contaminants found in human tissues and persist in the environment, posing significant risks to reproductive health. This review examines the impact of PFAS exposure on male reproductive health, with a focus on sperm epigenetics. PFASs disrupt endocrine function by altering key reproductive hormones and impairing sperm motility, quality, and viability. Epidemiologic and animal studies highlight inconsistent yet concerning associations between PFAS exposure and semen parameters, as well as altered gene expression and DNA methylation patterns. Moreover, PFAS exposure during critical windows of development has been linked to differential impacts on male versus female pubertal development, cognitive outcomes, and reproductive physiology, emphasizing the complexity of PFAS interactions. This comprehensive analysis highlights the need for continued research into the mechanisms by which PFASs influence reproductive health and development with potential implications for sperm epigenetics. The review emphasizes the importance of understanding the epigenetic mechanisms behind these disruptions, particularly DNA methylation and its role in heritable changes. Investigating the epigenetic modifications driven by PFAS exposure is crucial for elucidating the mechanisms by which these chemicals influence reproductive health. Future research should focus on understanding these epigenetic changes in both immediate fertility outcomes and transgenerational health risks.
Publication History
Article published online:
09 January 2025
© 2025. Thieme. All rights reserved.
Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
-
References
- 1 Buck RC, Korzeniowski SH, Laganis E, Adamsky F. Identification and classification of commercially relevant per- and poly-fluoroalkyl substances (PFAS). Integr Environ Assess Manag 2021; 17 (05) 1045-1055
- 2 OECD. Toward a new comprehensive global database OFPER- and polyfluoroalkyl substances (PFASS): Summary report on updating the OECD 2007 list of per- and polyfluoroalkyl substances (PFASS). 2018
- 3 Buck RC, Franklin J, Berger U. et al. Perfluoroalkyl and polyfluoroalkyl substances in the environment: terminology, classification, and origins. Integr Environ Assess Manag 2011; 7 (04) 513-541
- 4 Owens Jr CV. Review of source and transportation pathways of perfluorinated compounds through the air. J Environ Health 2021; 83 (06) 20-27
- 5 EPA, Multi-Industry Per- and Polyfluoroalkyl Substances (PFAS) Study – 2021 Preliminary Report. 2021. United States Environmental Protection Agency Office of Water; . Available at: https://www.epa.gov/system/files/documents/2021-09/multi-industry-pfas-study_preliminary-2021-report_508_2021.09.08.pdf . Accessed January 6, 2025
- 6 Calafat AM, Wong LY, Kuklenyik Z, Reidy JA, Needham LL. Polyfluoroalkyl chemicals in the U.S. population: data from the National Health and Nutrition Examination Survey (NHANES) 2003-2004 and comparisons with NHANES 1999-2000. Environ Health Perspect 2007; 115 (11) 1596-1602
- 7 Mazokopakis EE, Constantinidis TC. Definition of occupational lead toxicity in Greece. Environ Health Perspect 2007; 115 (10) A486
- 8 Steenland K, Tinker S, Frisbee S, Ducatman A, Vaccarino V. Association of perfluorooctanoic acid and perfluorooctane sulfonate with serum lipids among adults living near a chemical plant. Am J Epidemiol 2009; 170 (10) 1268-1278
- 9 Lee JE, Choi K. Perfluoroalkyl substances exposure and thyroid hormones in humans: epidemiological observations and implications. Ann Pediatr Endocrinol Metab 2017; 22 (01) 6-14
- 10 Lewis RC, Johns LE, Meeker JD. Serum biomarkers of exposure to perfluoroalkyl substances in relation to serum testosterone and measures of thyroid function among adults and adolescents from NHANES 2011-2012. Int J Environ Res Public Health 2015; 12 (06) 6098-6114
- 11 White SS, Fenton SE, Hines EP. Endocrine disrupting properties of perfluorooctanoic acid. J Steroid Biochem Mol Biol 2011; 127 (1-2): 16-26
- 12 Azhagiya Singam ER, Durkin KA, La Merrill MA, Furlow JD, Wang JC, Smith MT. Prediction of the interactions of a large number of per- and poly-fluoroalkyl substances with ten nuclear receptors. Environ Sci Technol 2024; 58 (10) 4487-4499
- 13 Tachachartvanich P, Singam ERA, Durkin KA, Furlow JD, Smith MT, La Merrill MA. In vitro characterization of the endocrine disrupting effects of per- and poly-fluoroalkyl substances (PFASs) on the human androgen receptor. J Hazard Mater 2022; 429: 128243
- 14 Hussain A, Gilloteaux J. The human testes: estrogen and ageing outlooks. Transl Res Anat 2020; 20
- 15 Mokra K. Endocrine disruptor potential of short- and long-chain perfluoroalkyl substances (PFASs) - a synthesis of current knowledge with proposal of molecular mechanism. Int J Mol Sci 2021;22(04):
- 16 Qiu Z, Qu K, Luan F. et al. Binding specificities of estrogen receptor with perfluorinated compounds: a cross species comparison. Environ Int 2020; 134: 105284
- 17 Ramos CF, Zamoner A. Thyroid hormone and leptin in the testis. Front Endocrinol (Lausanne) 2014; 5: 198
- 18 Corton JC, Lapinskas PJ. Peroxisome proliferator-activated receptors: mediators of phthalate ester-induced effects in the male reproductive tract?. Toxicol Sci 2005; 83 (01) 4-17
- 19 Monrose M, Thirouard L, Garcia M. et al. New perspectives on PPAR, VDR and FXRα as new actors in testicular pathophysiology. Mol Aspects Med 2021; 78: 100886
- 20 Sèdes L, Thirouard L, Maqdasy S. et al. Cholesterol: a gatekeeper of male fertility?. Front Endocrinol (Lausanne) 2018; 9: 369
- 21 Maxwell DL, Oluwayiose OA, Houle E. et al. Mixtures of per- and polyfluoroalkyl substances (PFAS) alter sperm methylation and long-term reprogramming of offspring liver and fat transcriptome. Environ Int 2024; 186: 108577
- 22 Mínguez-Alarcón L, Gaskins AJ, Meeker JD, Braun JM, Chavarro JE. Endocrine-disrupting chemicals and male reproductive health. Fertil Steril 2023; 120 (06) 1138-1149
- 23 Li Z, Li C, Wen Z. et al. Perfluoroheptanoic acid induces Leydig cell hyperplasia but inhibits spermatogenesis in rats after pubertal exposure. Toxicology 2021; 448: 152633
- 24 Lu T, Mortimer M, Li F. et al. Putative adverse outcome pathways of the male reproductive toxicity derived from toxicological studies of perfluoroalkyl acids. Sci Total Environ 2023; 873: 162439
- 25 Qiu L, Wang H, Dong T. et al. Perfluorooctane sulfonate (PFOS) disrupts testosterone biosynthesis via CREB/CRTC2/StAR signaling pathway in Leydig cells. Toxicology 2021; 449: 152663
- 26 Zhou Y, Sun W, Tang Q. et al. Effect of prenatal perfluoroheptanoic acid exposure on spermatogenesis in offspring mice. Ecotoxicol Environ Saf 2023; 260: 115072
- 27 Hærvig KK, Petersen KU, Hougaard KS. et al. Maternal exposure to per- and polyfluoroalkyl substances (PFAS) and male reproductive function in young adulthood: combined exposure to seven PFAS. Environ Health Perspect 2022; 130 (10) 107001
- 28 Vested A, Ramlau-Hansen CH, Olsen SF. et al. Associations of in utero exposure to perfluorinated alkyl acids with human semen quality and reproductive hormones in adult men. Environ Health Perspect 2013; 121 (04) 453-458
- 29 Liu Y, Calafat AM, Chen A. et al. Associations of prenatal and postnatal exposure to perfluoroalkyl substances with pubertal development and reproductive hormones in females and males: the HOME study. Sci Total Environ 2023; 890: 164353
- 30 Vuong AM, Yolton K, Xie C. et al. Prenatal and childhood exposure to poly- and perfluoroalkyl substances (PFAS) and cognitive development in children at age 8 years. Environ Res 2019; 172: 242-248
- 31 Ma X, Cui L, Chen L. et al. Parental plasma concentrations of perfluoroalkyl substances and in vitro fertilization outcomes. Environ Pollut 2021; 269: 116159
- 32 Zhang Y, Mustieles V, Martin L. et al. Maternal and paternal preconception serum concentrations of per and polyfluoroalkyl substances in relation to birth outcomes. Environ Sci Technol 2024; 58 (06) 2683-2692
- 33 Shi W, Zhang Z, Li M, Dong H, Li J. Reproductive toxicity of PFOA, PFOS and their substitutes: a review based on epidemiological and toxicological evidence. Environ Res 2024; 250: 118485
- 34 Blake BE, Cope HA, Hall SM. et al. Evaluation of maternal, embryo, and placental effects in CD-1 mice following gestational exposure to perfluorooctanoic acid (PFOA) or hexafluoropropylene oxide dimer acid (HFPO-DA or GenX). Environ Health Perspect 2020; 128 (02) 27006
- 35 Case MT, York RG, Christian MS. Rat and rabbit oral developmental toxicology studies with two perfluorinated compounds. Int J Toxicol 2001; 20 (02) 101-109
- 36 Luebker DJ, Case MT, York RG, Moore JA, Hansen KJ, Butenhoff JL. Two-generation reproduction and cross-foster studies of perfluorooctanesulfonate (PFOS) in rats. Toxicology 2005; 215 (1-2): 126-148
- 37 Du G, Hu J, Huang Z. et al. Neonatal and juvenile exposure to perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS): advance puberty onset and kisspeptin system disturbance in female rats. Ecotoxicol Environ Saf 2019; 167: 412-421
- 38 López-Doval S, Salgado R, Lafuente A. The expression of several reproductive hormone receptors can be modified by perfluorooctane sulfonate (PFOS) in adult male rats. Chemosphere 2016; 155: 488-497
- 39 Qiu L, Zhang X, Zhang X. et al. Sertoli cell is a potential target for perfluorooctane sulfonate-induced reproductive dysfunction in male mice. Toxicol Sci 2013; 135 (01) 229-240
- 40 Wan HT, Zhao YG, Wong MH. et al. Testicular signaling is the potential target of perfluorooctanesulfonate-mediated subfertility in male mice. Biol Reprod 2011; 84 (05) 1016-1023
- 41 Bao J, Zhang Y, Zhang L, Wang X. Effects of maternal exposure to PFOA on testes of male offspring mice. Chemosphere 2021; 272: 129585
- 42 Rappazzo KM, Coffman E, Hines EP. Exposure to perfluorinated alkyl substances and health outcomes in children: a systematic review of the epidemiologic literature. Int J Environ Res Public Health 2017; 14 (07) 691
- 43 Suh CH, Cho NK, Lee CK. et al. Perfluorooctanoic acid-induced inhibition of placental prolactin-family hormone and fetal growth retardation in mice. Mol Cell Endocrinol 2011; 337 (1-2): 7-15
- 44 Feng X, Wang X, Cao X, Xia Y, Zhou R, Chen L. Chronic exposure of female mice to an environmental level of perfluorooctane sulfonate suppresses estrogen synthesis through reduced histone H3K14 acetylation of the StAR promoter leading to deficits in follicular development and ovulation. Toxicol Sci 2015; 148 (02) 368-379
- 45 Haimbaugh A, Wu CC, Akemann C. et al. Multi- and transgenerational effects of developmental exposure to environmental levels of PFAS and PFAS mixture in zebrafish (Danio rerio). Toxics 2022; 10 (06) 334
- 46 Calvert L, Green MP, De Iuliis GN. et al. Assessment of the emerging threat posed by perfluoroalkyl and polyfluoroalkyl substances to male reproduction in humans. Front Endocrinol (Lausanne) 2022; 12: 799043
- 47 Pan Y, Cui Q, Wang J. et al. Profiles of emerging and legacy per-/polyfluoroalkyl substances in matched serum and semen samples: new implications for human semen quality. Environ Health Perspect 2019; 127 (12) 127005
- 48 Emerce E, Çetin Ö. Genotoxicity assessment of perfluoroalkyl substances on human sperm. Toxicol Ind Health 2018; 34 (12) 884-890
- 49 World Health Organization. . WHO Laboratory Manual for the Examination and Processing of Human Semen. 5th edition. 2010
- 50 Luo K, Huang W, Zhang Q. et al; Shanghai Birth Cohort. Environmental exposure to legacy poly/perfluoroalkyl substances, emerging alternatives and isomers and semen quality in men: a mixture analysis. Sci Total Environ 2022; 833: 155158
- 51 Zhang Y, Sun Q, Mustieles V. et al. Predictors of serum per- and polyfluoroalkyl substances concentrations among U.S. couples attending a fertility clinic. Environ Sci Technol 2024; 58 (13) 5685-5694
- 52 Di Nisio A, Sabovic I, Valente U. et al. Endocrine disruption of androgenic activity by perfluoroalkyl substances: clinical and experimental evidence. J Clin Endocrinol Metab 2019; 104 (04) 1259-1271
- 53 Joensen UN, Bossi R, Leffers H, Jensen AA, Skakkebaek NE, Jørgensen N. Do perfluoroalkyl compounds impair human semen quality?. Environ Health Perspect 2009; 117 (06) 923-927
- 54 Joensen UN, Veyrand B, Antignac JP. et al. PFOS (perfluorooctanesulfonate) in serum is negatively associated with testosterone levels, but not with semen quality, in healthy men. Hum Reprod 2013; 28 (03) 599-608
- 55 Louis GM, Chen Z, Schisterman EF. et al. Perfluorochemicals and human semen quality: the LIFE study. Environ Health Perspect 2015; 123 (01) 57-63
- 56 Specht IO, Hougaard KS, Spanò M. et al. Sperm DNA integrity in relation to exposure to environmental perfluoroalkyl substances - a study of spouses of pregnant women in three geographical regions. Reprod Toxicol 2012; 33 (04) 577-583
- 57 Toft G, Jönsson BA, Lindh CH. et al. Exposure to perfluorinated compounds and human semen quality in Arctic and European populations. Hum Reprod 2012; 27 (08) 2532-2540
- 58 Wang H, Wei K, Wu Z. et al. Association between per- and polyfluoroalkyl substances and semen quality. Environ Sci Pollut Res Int 2023; 30 (10) 27884-27894
- 59 Alamo A, La Vignera S, Mogioì LM. et al. In-vitro effects of perfluorooctanoic acid on human sperm function: What are the clinical consequences?. J Clin Med 2024; 13 (08) 2201
- 60 Šabović I, Cosci I, De Toni L. et al. Perfluoro-octanoic acid impairs sperm motility through the alteration of plasma membrane. J Endocrinol Invest 2020; 43 (05) 641-652
- 61 Kumaresan A, Yadav P, Sinha MK. et al. Male infertility and perfluoroalkyl and poly-fluoroalkyl substances: evidence for alterations in phosphorylation of proteins and fertility-related functional attributes in bull spermatozoa. Biol Reprod 2024; 111 (03) 723-739
- 62 Yang W, Ling X, He S. et al. Perturbation of IP3R-dependent endoplasmic reticulum calcium homeostasis by PPARδ-activated metabolic stress leads to mouse spermatocyte apoptosis: a direct mechanism for perfluorooctane sulfonic acid-induced spermatogenic disorders. Environ Pollut 2024; 343: 123167
- 63 Ortiz-Sánchez PB, Roa-Espitia AL, Fierro R. et al. Perfluorooctane sulfonate and perfluorooctanoic acid induce plasma membrane dysfunction in boar spermatozoa during in vitro capacitation. Reprod Toxicol 2022; 110: 85-96
- 64 Gasparini C, Iori S, Pietropoli E. et al. Sub-acute exposure of male guppies (Poecilia reticulata) to environmentally relevant concentrations of PFOA and GenX induces significant changes in the testis transcriptome and reproductive traits. Environ Int 2024; 187: 108703
- 65 Cui Q, Pan Y, Wang J, Liu H, Yao B, Dai J. Exposure to per- and polyfluoroalkyl substances (PFASs) in serum versus semen and their association with male reproductive hormones. Environ Pollut 2020; 266 (Pt 2): 115330
- 66 Liu X, Luo K, Zhang J, Yu H, Chen D. Exposure of preconception couples to legacy and emerging per- and polyfluoroalkyl substances: variations within and between couples. Environ Sci Technol 2022; 56 (10) 6172-6181
- 67 Hurley S, Goldberg D, Wang M. et al. Time trends in per- and polyfluoroalkyl substances (PFASs) in California women: declining serum levels, 2011-2015. Environ Sci Technol 2018; 52 (01) 277-287
- 68 Zhang S, Kang Q, Peng H. et al. Relationship between perfluorooctanoate and perfluorooctane sulfonate blood concentrations in the general population and routine drinking water exposure. Environ Int 2019; 126: 54-60
- 69 Zeeshan M, Yang Y, Zhou Y. et al. Incidence of ocular conditions associated with perfluoroalkyl substances exposure: isomers of C8 Health Project in China. Environ Int 2020; 137: 105555
- 70 Göckener B, Weber T, Rüdel H, Bücking M, Kolossa-Gehring M. Human biomonitoring of per- and polyfluoroalkyl substances in German blood plasma samples from 1982 to 2019. Environ Int 2020; 145: 106123
- 71 Tsai MS, Lin CY, Lin CC. et al. Association between perfluoroalkyl substances and reproductive hormones in adolescents and young adults. Int J Hyg Environ Health 2015; 218 (05) 437-443
- 72 Petersen MS, Halling J, Jørgensen N. et al. Reproductive function in a population of young faroese men with elevated exposure to polychlorinated biphenyls (PCBs) and perfluorinated alkylate substances (PFAS). Int J Environ Res Public Health 2018; 15 (09) 1880
- 73 Raymer JH, Michael LC, Studabaker WB. et al. Concentrations of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and their associations with human semen quality measurements. Reprod Toxicol 2012; 33 (04) 419-427
- 74 Olsen GW, Burris JM, Ehresman DJ. et al. Half-life of serum elimination of perfluorooctanesulfonate, perfluorohexanesulfonate, and perfluorooctanoate in retired fluorochemical production workers. Environ Health Perspect 2007; 115 (09) 1298-1305
- 75 Beale DJ, Nguyen TV, Bose U. et al. Metabolic disruptions and impaired reproductive fitness in wild-caught freshwater turtles (Emydura macquarii macquarii) exposed to elevated per- and polyfluoroalkyl substances (PFAS). Sci Total Environ 2024; 926: 171743
- 76 Collí-Dulá RC, Martyniuk CJ, Streets S, Denslow ND, Lehr R. Molecular impacts of perfluorinated chemicals (PFASs) in the liver and testis of male largemouth bass (Micropterus salmoides) in Minnesota Lakes. Comp Biochem Physiol Part D Genomics Proteomics 2016; 19: 129-139
- 77 Luo K, Liu X, Nian M. et al; Shanghai Birth Cohort. Environmental exposure to per- and polyfluoroalkyl substances mixture and male reproductive hormones. Environ Int 2021; 152: 106496
- 78 Olsen GW, Gilliland FD, Burlew MM, Burris JM, Mandel JS, Mandel JH. An epidemiologic investigation of reproductive hormones in men with occupational exposure to perfluorooctanoic acid. J Occup Environ Med 1998; 40 (07) 614-622
- 79 Sang L, Ge Y, Liu F. et al. Association between per- and polyfluoroalkyl substances and sex hormone levels in males based on human studies. Ecotoxicol Environ Saf 2024; 271: 115998
- 80 Lopez-Espinosa MJ, Mondal D, Armstrong BG, Eskenazi B, Fletcher T. Perfluoroalkyl Substances, Sex Hormones, and Insulin-like Growth Factor-1 at 6-9 Years of Age: A Cross-Sectional Analysis within the C8 Health Project. Environ Health Perspect 2016; 124 (08) 1269-1275
- 81 Marcho C, Oluwayiose OA, Pilsner JR. The preconception environment and sperm epigenetics. Andrology 2020; 8 (04) 924-942
- 82 Wu H, Hauser R, Krawetz SA, Pilsner JR. Environmental susceptibility of the sperm epigenome during windows of male germ cell development. Curr Environ Health Rep 2015; 2 (04) 356-366
- 83 Lismer A, Kimmins S. Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development. Nat Commun 2023; 14 (01) 2142
- 84 Ly L, Chan D, Trasler JM. Developmental windows of susceptibility for epigenetic inheritance through the male germline. Semin Cell Dev Biol 2015; 43: 96-105
- 85 Kaltsas A, Moustakli E, Zikopoulos A. et al. Impact of advanced paternal age on fertility and risks of genetic disorders in offspring. Genes (Basel) 2023; 14 (02) 486
- 86 Petroff RL, Cavalcante RG, Langen ES, Dolinoy DC, Padmanabhan V, Goodrich JM. Mediation effects of DNA methylation and hydroxymethylation on birth outcomes after prenatal per- and polyfluoroalkyl substances (PFAS) exposure in the Michigan mother-infant Pairs cohort. Clin Epigenetics 2023; 15 (01) 49