Endocrine-Disrupting Chemicals and Disorders of Penile Development in Humans

Abstract

This paper reviews the current knowledge on the environmental effects on penile development in humans. The specific focus is on endocrine-disrupting chemicals (EDCs), a heterogeneous group of natural or manmade substances that interfere with endocrine function, and whether they can induce hypospadias and micropenis in male neonates. Epidemiological data and animal observations first raised suspicions about environmental effects, leading to the testis dysgenesis syndrome (TDS) hypothesis. More recent research has provided stronger indications that TDS may indeed be the result of the direct or indirect effects of EDCs. Drawing on epidemiological and toxicological studies, we also report on the effects of maternal diet and substances like pesticides, phthalates, bisphenol A, and polychlorinated biphenyls. Proximity to contamination hazards and occupational exposure are also suspected to contribute to the occurrence of hypospadias and micropenis. Lastly, the cumulative effects of EDCs and the possibility of transgenerational effects, with the penile development of subsequent generations being affected, raise concerns for long-term public health.

Tetramethyl bisphenol A stimulates proliferation but inhibits fetal Leydig cell function in male rats by targeting estrogen receptor α after in utero exposure

“…In recent years, increasing evidence points to BPA and its analogs as endocrine disrupting compounds that may inhibit biosynthesis, thereby affecting the male gonad development and maturation and eventually leading to TDS. 2,4,27 This research aimed to explore the effect of TMBPA (a BPA analog) on FLC function. We gavaged pregnant female rats with TMBPA from GD 14 to GD 21 and found that TMBPA promoted the proliferation of differentiating FLCs and putative stem cells possibly through activating ESR1, thereby activating the AKT1/AKT2 pathway and further increasing cell cycle regulatory CDK2/CDK4 protein levels.…”

“…In recent years, increasing evidence points to BPA and its analogs as endocrine disrupting compounds that may inhibit biosynthesis, thereby affecting the male gonad development and maturation and eventually leading to TDS 2,4,27 . This research aimed to explore the effect of TMBPA (a BPA analog) on FLC function.…”

Current perspectives in hypospadias research: A scoping review of articles published in 2021 (Review)

“…Maternal exposure to different chemicals can induce malformation of the penis. The most incriminated chemicals in this process are bisphenol, inorganic solvents, alkyl phenolic compounds, phthalates, benzophenones, parabens, siloxanes, pesticides or herbicides, diethylstilbestrol, cadmium, DDT, vinclozolin (fungicide), petroleum solvents and SO 2 (194)(195)(196)(197)(198)(199)(200)(201). Some studies are more general and incriminate the air pollution, heat, or the proximity of a vineyard in the development of hypospadias (202)(203)(204).…”

Using Experimental Models to Decipher the Effects of Acetaminophen and NSAIDs on Reproductive Development and Health

“…Indeed, Wagner-Mahler et al found that cryptorchidism detection at birth was associated with exposure to other endocrine disruptors, such as polychlorinated biphenyls and 1,1-dichloro-2,2-bis (pchlorophenyl) ethylene ( Wagner-Mahler et al, 2011 ). Exposure to environmental endocrine disruptors has been associated with the occurrence of hypospadias and micropenis in male neonates ( Raghavan et al, 2018 ; Gaspari et al, 2021 ) and with puberty disorders in girls ( Sultan et al, 2018 ). Epidemiology studies on cryptorchidism occurrence in France in the last 12 years ( n = 89,000 boys undergoing surgery for cryptorchidism), revealed an increase in its incidence by 36% that may be linked to geographically determined environmental factors ( Le Moal et al, 2021 ).…”

“…The etiology of these syndromes is not fully known, but the steady increase in reproductive disorders suggests causes related to lifestyle and/or environmental factors rather than genetic alterations ( Johansson et al, 2017 ; Arendrup et al, 2018 ). Many epidemiological and animal studies showed that in utero exposure to endocrine disruptors interferes with endocrine gland functions that have been implicated in hypospadias and micropenis development in male neonates ( Skakkebaek, 2016 ; Van Den Driesche et al, 2017 ; Raghavan et al, 2018 ; Gaspari et al, 2021 ). Environmental factors acting during prenatal or adult life are involved in early puberty ( Sultan et al, 2018 ) and ovarian reserve decrease ( Arendrup et al, 2018 ), and could contribute to premature ovarian insufficiency ( Hoyer and Keating, 2014 ; Vabre et al, 2017 ; Huhtaniemi et al, 2018 ).…”