Exposure to environmental pollution in the uterus and during the first 8.5 years of life causes alterations in the structural connectivity of the white matter in the brain


A study published in the journal Environmental Pollution has found an association, in children aged 9‑12, between exposure to air pollutants in the womb and during the first 8.5 years of life and alterations in white matter structural connectivity in the brain.

The greater the child’s exposure before age 5, the greater the brain structure alteration observed in preadolescence.

The study was led by the Barcelona Institute for Global Health (ISGlobal), a research centre supported by the ”la Caixa” Foundation.

Tracts or bundles of cerebral white matter ensure structural connectivity by interconnecting the different areas of the brain. Connectivity can be measured by studying the microstructure of this white matter, a marker of typical brain development. Abnormal white matter microstructure has been associated with psychiatric disorders (e.g., depressive symptoms, anxiety and autism spectrum disorders).

In addition to the association between air pollution and white matter microstructure, the study also found a link between specific exposure to fine particulate matter (PM2.5) and the volume of the putamen, a brain structure involved in motor function, learning processes and many other functions. As the putamen is a subcortical structure, it has broader and less specialised functions than cortical structures.

The study found that the greater the exposure to PM2.5, especially during the first 2 years of life, the greater the volume of the putamen in preadolescence.

“A larger putamen has been associated with certain psychiatric disorders (schizophrenia, autism spectrum disorders, and obsessive-compulsive spectrum disorders),” says Anne-Claire Binter, ISGlobal researcher and first author of the study.

“The novel aspect of the present study is that it identified periods of susceptibility to air pollution” Binter goes on to explain.

“We measured exposure using a finer time scale by analysing the data on a month-by-month basis, unlike previous studies in which data was analysed for trimesters of pregnancy or childhood years. In this study, we analysed the children’s exposure to air pollution from conception to 8.5 years of age on a monthly basis.

Effects Observed Even at Pollution Levels Complying With European Union Standards

Another strong point of this study is that the data analysed came from a large cohort of 3,515 children enrolled in the Generation R Study in Rotterdam (Netherlands).

To determine each participant’s exposure to air pollution during the study period, the researchers estimated the daily levels of nitrogen dioxide (NO2) and particulate matter (PM2.5 and PM2.5 absorbance) at their homes during the mother’s pregnancy and until they reached 8.5 years of age.

When participants were between 9 and 12 years analysed of age they underwent brain magnetic resonance imaging to examine the structural connectivity and the volumes of various brain structures at that time.

The levels of NO2 and PM2.5 recorded in the present study exceeded the annual thresholds limits specified in the current World Health Organization guidelines (10 µg/m3 and 5 µg/m3, respectively) but met European Union (EU) standards, an indication that brain development can be affected by exposure to air pollution at levels lower than the current EU air quality limit values.

“One of the important conclusions of this study” explains Binter “is that the infant’s brain is particularly susceptible to the effects of air pollution not only during pregnancy, as has been shown in earlier studies, but also during childhood.”

“We should follow up and continue to measure the same parameters in this cohort to investigate the possible long-term effects on the brain of exposure to air pollution” concludes Mònica Guxens, ISGlobal researcher and last author of the study.

Reproductive success in humans and wild animals is defined as an organism’s capacity to produce offspring that will reproduce in the subsequent generation; thereby, ensuring an individual’s genetic line. Measuring reproductive success in humans and domesticated species is relatively routine; however, for wild species this is challenging.

Despite such challenges and the numerous factors influencing reproductive success in any given organism from natural abiotic (i.e., photoperiod, temperature, etc.) and biotic factors (e.g., parental, nutritional status, etc.), there is substantial evidence suggesting environmental chemicals decrease reproductive success in every major vertebrate taxa and in many invertebrate species (Fig. 1 and Table 1, Table 2). Many of these chemicals act by altering the function of the endocrine system components that mediate reproductive development. These chemicals belong to a group of chemicals called endocrine disrupting chemicals (EDCs).

In Canada, an EDC is defined as a “substance having the ability to disrupt the synthesis, secretion, transport, binding, action, or elimination of natural hormones in an organism, or its progeny, that are responsible for the maintenance of homeostasis, reproduction, development or behaviour of the organism” (section 43 of the Canadian Environmental Protection Act, 1999 (CEPA, 1999). Concern regarding the risks of EDCs to wildlife and humans is widespread, and global efforts to advance assessment methodologies are underway in several countries (Barton-Maclaren et al., 2022).

Fig. 1. Timeline of key examples of EDCs affec; ng reproduc; ve measures or bioaccumula; ng in wildlife and humans summarized in this review and/or in previously published reviews (indicated by numerical superscripts: 1. Bergman et al. (2012); 2, Matthiessen et al., 2018; 3. Kidd et al. (2007); 4, Reeder et al. (2005); 5, Van Der Kraak et al. (2014); 6, Park and Kidd (2005); 7, Lawson et al. (2020).

Table 1. Description of human male and female reproductive disorders for which EDCs exposure is a risk factor.

FertilityCapacity to establish a clinical pregnancy.Vander Borght and Wyns (2018).
InfertilityFailure to establish a clinical pregnancy after 12 months of regular and unprotected sexual intercourse.Vander Borght and Wyns (2018).
Decline in fertilityIncrease of 0.37% and 0.29% per year in age-standardized prevalance of infertility for females and males, respectively, for the period from 1990 to 2017.Sun et al. (2019).
2009–2010 Canadian Community Health Survey: infertility prevalence range from 11.5% to 15.7%, significant increase compared with previous national estimates of 5.4% (in 1984) and 8.5% (in 1992).Bushnik et al. (2012)
MiscarriageLoss of pregnancy before viability.
23 million miscarriages per year worldwide; pooled risk of miscarriage of 15.3%.
Quenby et al. (2021).
CryptorchidismNon-descent of one or both testicles in the scrotum at birth.Skakkebæk et al., 2015
HypospadiasCongenital malformation of the penis where the opening of the urethra is in the underside of the penis instead of its tip.Bergman et al. (2015); Skakkebæk et al., 2015.
Testicular cancer2019 Canadian Cancer Statistics Annual Report: 1.3% yearly increase in its incidence between 1984 and 2015.Purdue et al., 2005; Rosen et al. (2011); Gurney et al. (2019).
Decrease in sperm count and qualityDecline of 52.4% in sperm concentration between 1973 and 2001 in Western countries.Levine et al. (2017); Sengupta et al. (2018).
Decrease in testosterone levelsAge-independent decline in total serum testosterone.Travison et al. (2007).
Early menopauseEntry to menopause age 40–45 years old.Faubion et al. (2015); Rossetti et al. (2017).
Primary ovarian insufficiencyPrior to age 40 cessation of ovarian activity.
Oligo/amenorrhea (for at least 4 months).
Evated serum follicle-stimulating hormone (FSH) levels (>25IU/l) on two occasions >4 weeks apart.
Nelson (2009); Vabre et al. (2017)
Polycystic ovarian syndromeOligo/anovulation, hyperandrogenism, polycystic ovarian morphology, as well as metabolic dysfunction.
Increase of 1.45% from 2007 to 2017 in global age-standardized incidence rate.
Legro (2016); Liu et al. (2021).
EndometriosisEctopic endometrium (presence of endometrial glands and stroma outside the uterus).Holoch and Lessey (2010); May et al. (2010); Zondervan et al. (2020); Plante et al. (2021)
Uterine fibroidsBenign tumors of the female reproductive tract.
Cause of menorrhagia, pelvic pain, and pregnancy complications.
Grube et al. (2019); Kaganov and Ades (2016)

Table 2. Summary of effects of EDCs on reproduction in field studies presented in this review across taxa with reference to example publications* describing these phenomena. Solid circles indicate effect observed and blank cell indicates not observed/not definitive evidence.

* References for example studies pertaining to numbers above are provided in Supplementary Table 1.

It is widely accepted that EDCs of anthropogenic origin are chemically diverse, ubiquitous in the environment (Metcalfe et al., 2021), and that exposure of wildlife and humans to multiple chemicals is occurring via food/water intake, inhalation, and direct contact. Legacy persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) have been reported in all environmental compartments globally (El-Shahawi et al., 2010), and many have continuing adverse effects on growth and reproduction (Bergman et al., 2015; Kortenkamp et al., 2011; Matthiessen et al., 2018).

Anthropogenic chemical pollutants enter the environment through multiple routes. For example, alkylphenol ethoxylates, widely used for cleaning formulations and as industrial process aids, have been detected in municipal and industrial wastewaters, water from sewage treatment plants or landfill leachates (Acir and Guenther, 2018).

PCBs and brominated flame retardants have also been reported in house dust, indoor, and outdoor air (Fan et al., 2014; Rudel and Perovich, 2009), and atmospheric transportation plays a major role in their global fate.

Complicating the risk assessment and regulation of EDCs is that levels of these chemicals in the environment vary over different time scales resulting in dynamic, multi-chemical exposure scenarios (Metcalfe et al., 2021). For humans, quantifying exposure to EDCs is relatively recent (i.e., over the last two decades), but is also revealing common widespread persistent exposure to a broad mixture of indoor and outdoor chemicals similar to those observed in wildlife (Chen et al., 2011; Gao and Kannan, 2020; Patandin et al., 1999; Rudel and Perovich, 2009).

Ho et al. (this issue) reviews human exposure to EDCs in general human populations by describing the biomonitoring studies measuring chemical concentrations in blood, breast milk, urine, and adipose tissues. For example, current use chemicals such as parabens, bisphenols and phthalates have been detected in urine (van der Meer et al., 2021), halogenated flame retardants in adipose tissues and human milk (Pan et al., 2020), and legacy contaminants such as PCBs, dioxins, and furans in serum (Lambertino et al., 2021).

Placental transfer has been demonstrated for various classes of EDCs (Mitro et al., 2015, Plante et al., 2021), confirming human exposure to these chemicals from the very early stages of life. Data on actual exposure are essential to define environmentally relevant concentrations for a broader range of EDCs in humans and wildlife alike.

Understanding the impacts of chemical exposures on reproductive success in wildlife and humans is a daunting task. It is complicated by diversity in reproductive strategies, varying knowledge of the endocrine control of reproductive development in different species and/or the ease at which reproductive success can be measured. As an example, human reproduction is well characterized, yet it is challenging to distinguish the impacts of EDCs amongst several confounding chemical co-exposures and lifestyle variables, due to the inability to perform experimental studies in humans to corroborate epidemiological findings and establish cause and effect relationships with EDCs.

Nevertheless, for vertebrate taxa in general, there are several predominant neural and endocrine components conserved across species which regulate reproduction. In particular, the hypothalamic-pituitary-gonad (HPG) axis involves several neurohormones (i.e., sex steroids, gonadotropins, etc.) and signaling mechanisms (i.e., nuclear and membrane bound receptors, etc.) that regulate reproduction, in addition to other physiological processes (i.e., neuroplasticity, bone growth, metabolism, etc.).

Many of these processes are targets of EDC actions. Invertebrates also possess neuroendocrine systems. The evolution of complex neuroendocrine systems occurred in several invertebrates including annelids, mollusks, insects, arachnids and crustaceans, and these systems are also targets of EDC actions (deFur, 2004).

Although a full comparative review of the neural and endocrine controls of reproduction in vertebrates and invertebrates (reviewed in deFur, 2004 and IPCS, 2002) is beyond the scope of this critical review, several types of hormones (i.e. steroids, peptides, simple amides, and terpenes) and signaling mechanisms (nuclear and membrane bound receptors) comprise invertebrate neuroendocrine and reproductive systems. While a sound understanding of reproductive biology in the species under investigation is essential, a comparative reproductive approach to EDCs can yield valuable insights into mode of action and risks associated with chemical exposure.

The main objective of this review was to synthesize the current understanding of the impacts of EDCs on reproductive success in wildlife and humans by identifying adverse effects associated with, or known to lead to, reduced reproductive capacity in sexually mature individuals. For brevity, we focus exclusively on physiological and apical evidence from field-based investigations rather than molecular and laboratory-based studies. However, for some taxa epidemiological and/or field-based observations were scarce/non-existent and laboratory-based studies were presented as examples to maximize the survey of species included.

To focus on how the impacts of EDCs may have changed over time, the examples selected often included a retrospective assessment of the knowledge of trends observed in Canada over the last decades. Despite the challenges associated with epidemiological and field-based studies, where possible we summarize the known molecular mechanisms of action and critical windows of exposure to EDCs leading to the observed adverse reproductive health outcomes in sexually mature individuals. Finally, where appropriate, gaps in knowledge were identified as these may limit our assessment of EDC effects on biota.

Effects of EDCs on reproduction

About 16% of heterosexual couples of reproductive age experience infertility, an incidence that has almost doubled between 1992 and 2012. Consequently, infertility has been identified as a priority for the medical research community, for service providers, and for policy makers (Quenby et al., 2021). This trend can be attributed to changes in lifestyle, diet, reproducing at older ages and to exposure to environmental pollutants such as EDCs. Epidemiological evidence of EDCs affecting human reproduction are detailed in Table 1 and below for both men and women.

The reproductive health of men living in developed countries is declining (Levine et al., 2017; Niels E. Skakkebæk et al., 2015; Swan and Colino, 2021). Epidemiological studies suggest that there has been an increase in the incidence of male reproductive disorders for more than 50 years. These disorders summarized in Table 1 include cryptorchidism, hypospadias, testicular cancer, a decrease in circulating testosterone levels, and a decrease in the number and quality of spermatozoa. In 2001, Skakkebaek and colleagues hypothesized that these pathologies were symptoms of a single syndrome with a common fetal origin that they named the testicular dysgenesis syndrome (TDS), which has a fetal origin (Skakkebæk et al., 2001, Skakkebæk et al., 2015). Since then, epidemiological evidence has shown that the four symptoms of TDS are interconnected in a network of risk factors, i.e. the occurrence of one of the pathologies represents a risk factor that may lead to the appearance of one or more other symptoms of TDS. Interestingly, the occurrence of one or more TDS pathologies is also associated with the feminization of AGD (Schwartz et al., 2019; Swan, 2006; Swan et al., 2005). In humans, AGD is the distance from the center of the anus to the genitalia (Fischer et al., 2020). This distance is normally 1.5 to 2 times longer in males than in females and is used as a biomarker of androgen action during fetal development (Schwartz et al., 2019). Several studies have shown that males with cryptorchidism, hypospadias, low sperm count or low androgen levels have a short AGD (Eisenberg et al., 2011, 2012; Swan, 2006; Swan et al., 2005; Thankamony et al., 2014). Various factors may be responsible for the increase in these abnormalities, including in utero exposure to EDCs exhibiting estrogenic or anti-androgenic activity that interfere with the endocrine system of the developing organism (Delbes et al., 2022).

Exposure of pregnant women to the synthetic estrogen DES is a telling example of the adverse effects of in utero exposure to an endocrine disruptor on the reproductive health of the offspring (Ho et al., 2022, Delbes et al., 2022). Follow-up of childhood cohorts showed that exposed boys had a higher risk of cryptorchidism (Gill et al., 1979; Palmer et al., 2009), hypospadias (Brouwers et al., 2006; Klip et al., 2002; Palmer et al., 2009; Toppari et al., 2001) and low sperm count in adulthood (Gill et al., 1979; Leary et al., 1984). Another estrogenic compound studied in association with TDS in humans is BPA for which a negative correlation has been shown between its level in cord blood and the level of expression of the hormone Insulin-like 3 (INSL3) in boys with cryptorchidism (Chevalier et al., 2015). Also, a dose-dependent association between short AGD has been shown in boys whose mothers were exposed to BPA during pregnancy via their occupation (factories employees exposed to BPA) (Miao et al., 2011). Finally, exposure to BPA in adulthood has been associated with decreased sperm concentration in humans (Li et al., 2011; Meeker et al., 2010).

Many studies suggest an association between exposure to phthalates and hormonal disruption resulting in incomplete virilization (under-masculinization) of boys exposed in utero (Main et al., 2006; Matsumoto et al., 2008; Swan et al., 2005). For example, Main and colleagues found an association between the levels of monomethyl phthalate, mono-ethyl phthalate and mono-n-butyl phthalate in breast milk and the free LH: testosterone ratio in 3-year-old boys suggesting an alteration in testicular function during breastfeeding, however without incidence of cryptorchidism (Main et al., 2006). In another Danish study, high levels of phthalate metabolites and diisononyl phthalate (DiNP) in amniotic fluid were correlated with high odds ratios for cryptorchidism and hypospadias, but without association with steroid hormone or INSL3 levels in amniotic fluid (Jensen et al., 2015). At the same time, an inverse association has been demonstrated between AGD, penile width and maternal urine phthalate levels in the 1st and 2nd trimesters of pregnancy but not in the 3rd trimester (Jensen et al., 2016; Martino-Andrade et al., 2016). This is consistent with the adverse effects of hormonal disruption during the masculinization window, which is defined between gestational week (GW) 8 and 14 in humans (reviewed in Delbes et al., 2022). In longer term, it was shown that the presence of di (2-ethylhexyl) phthalate (DEHP) and DiNP metabolites in maternal serum is negatively associated with low testicular volume and low sperm volume (Axelsson et al., 2015). The concentration of monoethyl phthalate and mono-carboxy-isooctyl phthalate in maternal serum (collected between SG18 and SG34) has been negatively associated with sperm volume and sperm motility of sons in adulthood respectively (Hart et al., 2018). Very recently, maternal occupational exposure to phthalates has been correlated with low semen volume and total sperm count in their sons (Istvan et al., 2021).

Other anti-androgenic chemicals have been associated with TDS. This is the case of organochlorine pesticides such as DDE, PCBs, hexachlorobenzene, chlorodanes or DDT linked to risk of developing testicular cancer (Cohn et al., 2010; Giannandrea et al., 2011; Hardell et al., 2003; McGlynn et al., 2008). Small but significant higher risk of hypospadias in boys whose mothers were exposed to pesticides during pregnancy was also shown in a meta-analysis (Rocheleau et al., 2009). Three studies in France, Denmark and Finland showed an association between the level of pesticides in breast milk and colostrum and boys’ risk of cryptorchidism (Andersen et al., 2008; Brucker-Davis et al., 2008; Damgaard et al., 2006). A very recent study showed long term effect of maternal occupational exposure to pesticides on low semen volume and total sperm count in their sons (Istvan et al., 2021). Finally, there is considerable evidence that adult exposure to pesticides has adverse effects on male fertility by reducing sperm count and inducing azoospermia (reviewed in Goldsmith et al., 1984; Martenies and Perry, 2013; Potashnik et al., 1978; Whorton et al., 1979).

Other chemical compounds have been implicated in TDS through endocrine disruption. These include flame retardants that have been associated with hypospadias (Carmichael et al., 2003), cryptorchidism (Goodyer et al., 2017; Main et al., 2006) and testicular cancer (Hardell et al., 2006); heavy metals that have recently been associated with long term negative impact on semen volume and sperm count after in utero exposure (Istvan et al., 2021), and analgesics such as acetaminophen and ibuprofen that have been shown to alter human fetal gonad development, although the available data are still controversial (reviewed in Zafeiri et al., 2021). Together these epidemiological data support the fetal origin of TDS due to exposures to EDCs during key developmental phases having long-term consequences on reproductive success, as well as adult exposure causing adverse reproductive outcomes.

In contrast to apparent male reproductive health decline, global trends in female reproductive disorders (defined in Table 1) are more difficult to establish, partly due to constantly evolving diagnostic criteria (Amato et al., 2008) and the lack of reliable non-invasive diagnostic tools (Ghiasi et al., 2020a; Zondervan et al., 2020). Nevertheless, considerable prevalence for numerous reproductive pathologies, affecting women’s ability to conceive and overall birth rates is reported recently.

Female reproductive lifespan is largely determined by the size and the quality of the primordial follicle pool established early in life (the ovarian reserve) (Jirge, 2016). A dynamic decline in this pool occurs within the human ovary with age, culminating in the natural menopause at age 50 ± 4 years (Depmann et al., 2015). However, it has been estimated that large numbers of women worldwide are suffering from early menopause (EM) or will experience primary ovarian insufficiency (POI), 12.2% and 3.7% respectively (Golezar et al., 2019). Furthermore, certain maternal and environmental factors can disrupt oogenesis contributing to compromised oocyte quality and leading to arrested development, reduced fertility (see Table 1), and epigenetic defects that affect offspring long-term health (Delbes et al., 2022; Mtango et al., 2008, Plante et al., 2021). An increase of 1.45% from 2007 to 2017 in global age-standardized incidence rate for polycystic ovarian syndrome (PCOS) (Liu et al., 2021) was reported, which affects between 5% and 20% of women of reproductive age (Azziz et al., 2016). Furthermore, ovulation disorders like PCOS and POI, are estimated to account for infertility in about 1 of 4 infertile couples (Duursen et al., 2020). Endometriosis and uterine fibroids (UFs), often present as comorbidities in diseased patients, are further contributing to women’s infertility (Uimari et al., 2011). Found in up to 80–90% of women at the age of 50 (Grube et al., 2019; Parker, 2007), UF are associated with increased risk of pregnancy loss and obstetric complications and may be the sole cause of infertility in 2–3% of women (Freytag et al., 2021). Endometriosis prevalence at the population level ranges between 0.7% and 8.6%, yet among infertile woman is up to 68% (Eisenberg et al., 2018; Ghiasi et al., 2020b). This pathology is further associated with decreased oocyte quality (Xu et al., 2015) and increased risk for reproductive-site cancers (Kvaskoff et al., 2014; Zondervan et al., 2020).

A growing body of evidence in the last few decades implicates EDCs in the aetiology of reproductive pathologies (Diamanti-Kandarakis et al., 2009). Precise endocrine signalling is involved in all aspects of the development and functioning of the female reproductive system. Indeed, despite their multifactorial nature, estrogens seem to play a central role in disease pathogenesis of endometriosis and UFs (Borahay et al., 2017; Upson, 2020). In addition, overexposure to androgens in utero is thought to be responsible for PCOS development later in life (Filippou and Homburg, 2017) and can also affect among others, the early establishment of ovarian reserve (Johansson et al., 2020; Richardson et al., 2014). Therefore, the extreme sensitivity of the female reproductive system to disruption by chemicals that may interfere with estrogen and androgen synthesis and actions, together with the timing of the exposure are important considerations for the later outcome (Fowler et al., 2012). Similar to male TDS, ovarian dysgenesis syndrome (ODS) hypothesis proposes that some adult female reproductive health problems, such as reduced fertility, PCOS, POI, endometriosis and reproductive-site cancers, might have a common origin and result from early alterations of ovarian structure or function related to in utero chemical exposure, including EDCs (Delbes et al., 2022; Johansson et al., 2017, 2020). Further, these effects may be triggered or worsened by EDCs exposure throughout a woman’s life (Johansson et al., 2020). The most well-known example linking human fetal EDCs exposures with adult-onset reproductive disorders is provided by DES. Indeed, in utero DES exposure in females is associated with increased risk for development of clear cell adenocarcinoma (CCA) of the vagina and cervix, higher rates of genital tract abnormalities and adverse pregnancy outcomes (al Jishi and Sergi, 2017; Veurink et al., 2005), diagnosis of endometriosis, UFs and EM (Baird and Newbold, 2005; Hatch et al., 2006; Missmer et al., 2004). Human studies on prenatal exposure to EDCs and female reproductive disorders are still a major data gap, nevertheless higher levels of chemicals, particularly those associated with plastics and food packaging, are found in many diseased patients compared to control subjects. For example, BPA is thought to affect the ovarian reserve, as higher urinary BPA levels were inversely associated with antral follicle count (AFC) (Czubacka et al., 2021; Souter et al., 2013) and, number of retrieved oocytes and number of normally fertilized oocytes in in vitro fertilization cycles in women undergoing medically assisted reproduction (MAR) (Ehrlich et al., 2012; Mok-Lin et al., 2010). Further, maternal serum BPA levels early in pregnancy were associated with a higher risk of aneuploid and euploid miscarriage (Lathi et al., 2014). Higher BPA levels were reported in women with PCOS compared to controls (Hu et al., 2018), however, human evidence linking endometriosis risk with BPA exposure is inconsistent (Peinado et al., 2020; Rashidi et al., 2017; Simonelli et al., 2017). As for phthalates, higher urinary concentrations of some phthalate metabolites were associated with significant decrease in AFC (Messerlian et al., 2016), as well as reduced oocyte yield, fertilized oocytes, and top-quality embryos (Hauser et al., 2016; Machtinger et al., 2018) in women undergoing MAR. Further, higher monoethyl phthalate levels in maternal serum during pregnancy were associated with reduced serum anti-müllerian hormone (AMH) levels (a marker of ovarian reserve) in their adolescent daughters (Hart et al., 2014). Phthalate exposure is associated with lower odds of having PCOS in most studies (Akgül et al., 2019; Hart et al., 2014; Vagi et al., 2014). Overall positive correlations were reported between plasma concentrations of phthalate esters and endometriosis diagnosis, in particular for di-n-butyl phthalate (DnBP), butyl benzyl phthalate (BBzP), DEHP and di-n-octyl phthalate (DnOP; Cobellis et al., 2003; Kim et al., 2011; Reddy et al., 2006a, 2006b), as well as with urinary phthalate metabolites (Buck Louis et al., 2013; Cai et al., 2019; Kim et al., 2015). Evidence for phthalate exposure association with the risk of UFs is inconsistent (Kim et al., 2016; Pollack et al., 2015; Sun et al., 2016; Weuve et al., 2010). These correlations in women between both BPA and phthalates and effects on the ovaries and uterus are well supported by numerous in vivo and in vitro animal studies demonstrating these compounds have estrogenic modes of action (Delbes et al., 2022; Cheon, 2020; Tomza-Marciniak et al., 2018). Many other EDCs identified in experimental animal studies from various chemical categories have also been suspected to affect female reproductive system. Detection of PFAS in follicular fluid in woman undergoing MAR was associated with lower fertilization rate and number of embryos transferred (Governini et al., 2011). Higher serum concentrations for certain PFAS have been associated with increased risk for EM (Knox et al., 2011; Taylor et al., 2014) and were reported in PCOS (Vagi et al., 2014) and endometriosis patients (Campbell et al., 2016a). Pyrethroid pesticide exposure has been suspected to play a role in POI (Li et al., 2018). Exposure to organochlorine chemicals, including PCBs, OCP and dioxins has been associated with endometriosis diagnosis (Cano-Sancho et al., 2019), as well as with increased risk for EM (Akkina et al., 2004; Eskenazi et al., 2005; Grindler et al., 2015) and POI (Pan et al., 2019). PCBs and DDE exposure has been associated with PCOS (Yang et al., 2015) and UFs development (Trabert et al., 2015).

In conclusion, based on the epidemiological evidence and supporting non-human studies for several suspect or known EDCs, chemical exposure is undoubtedly affecting women’s reproductive health. However, the precise EDC thresholds, mechanisms, and extent for most chemicals in commerce requires further inquiry.

Common indicators and EDCs affecting reproduction

Although the data outlined in this review demonstrate the effects of EDCs on the reproductive endocrine axis vary somewhat in all taxa, several endpoints and EDCs are common to vertebrate and even invertebrate species (Table 2). For example, estrogenic EDCs such as organochlorine pesticides and sewage effluents are strongly associated with observations of direct effects on the ovaries and testes as indicated by gonad abnormalities in all taxa (Table 2). These observations of chemicals interfering with some aspects of the reproductive endocrine axis are particularly pronounced for aquatic species and are often corroborated by laboratory-based data sets (i.e. fish, amphibians, birds), and many of these same indicators are also observed in epidemiological studies in mammals. For example, positive correlations between many of these same EDCs (i.e., DDT, BPA, phthalates) to effects on ovarian and testicular structure and function in wild mammals and humans are evident. The DES case study whereby administration to pregnant women in utero leading to offspring with gonadal abnormalities (structural and functional) and cancers in both males and females provides further evidence of the potent effects of estrogenic chemicals during human development. Based on the studies in lower vertebrates linking molecular, organ and organismal level impacts of EDCs to reproductive success (i.e., organochlorine pesticides, organotin compounds, sewage, and pulp mill effluent effluents), it is likely that EDCs are contributing to reduced reproductive success in mammalian wildlife and humans despite the lack of controlled experimental studies to support epidemiological findings in these higher vertebrates.

Ultimately, some of the most common EDCs (i.e., DDT, BPA, phthalates) bind to and inhibit or activate estrogen or androgen receptors in multiple vertebrate species. This is no doubt, in part, due to the focus on detecting estrogenic and androgenic mechanisms of action in controlled experimental and field studies and the lack of methods to detect other mechanisms of endocrine action until recently (reviewed in Robitaille et al., 2021). Nonetheless, the evidence to date continues to corroborate the notion that EDCs identified as sex steroid agonists or antagonists have high potential for inducing a molecular initiating event leading to adverse reproductive outcomes in wildlife and humans. With steroids and their receptors widely dispersed throughout vertebrates and sex steroid-like receptors recently discovered in some invertebrates, it is not surprising that EDCs exerting their actions via sex steroid receptor interactions elicit adverse effects on reproduction in multiple vertebrate and invertebrate taxa. Consequently, it is clear that the sex steroid receptor screening assays reviewed and recommended as predictive, high-throughput tools for identifying chemicals with high potential for adverse impacts on reproduction by Robitaille et al. (2021) and Barton-Maclaren et al. (2022) are supported. Undoubtedly high throughput cell-based assays will aid in identifying those chemicals of high concern as reproductive EDCs, which can then be prioritized for subsequent investigations in the natural environment.

Despite the advances in our understanding of the ecological relevance of EDC mechanisms of action in recent years, long-term, continuous field studies complimented with controlled experimental studies are still needed to fully assess the impacts of EDCs at the population level in representative wildlife. Indeed, few field studies are long enough in duration to capture the full reproductive life cycle in vertebrate wildlife, let alone multiple generations to understand natural baseline or contaminant induced changes. Ideally, field surveys over multiple generations monitoring population levels, reproductive and non-reproductive health measures in more wildlife species integrated with in situ exposures and/or mesocosms as well as controlled laboratory experiments are recommended to establish cause and effect. Fig. 1 and Table 2 highlights several species and examples of field-based observations that can form the basis of more deliberate, extensive and long-term population level field studies to monitor contaminant effects, including adverse effects on the endocrine system. For example, the EEM Program in Canada includes standardized, long-term monitoring and effect thresholds for fish and benthic invertebrate populations to monitor the impacts of pulp and paper mill effluents, including some reproductive endpoints in fish. This program could be applied to monitor sewage effluent effects in fish and invertebrates or other contaminated waters, and enhanced with additional reproductive system endpoints (i.e., vitellogenin, hormone levels, gonad histopathology). This integrative approach would provide the evidence needed to assess the risk of the low-level, multi-EDC exposure scenarios wildlife are experiencing, track recoveries after efforts to remediate and work towards establishing adverse outcome pathways that can be translated into in vitro/in silico screening and modelling methodologies. Lastly, fundamental studies on reproductive endocrinology are lacking for most wild animals but are particularly sparse for most invertebrates, non-crocodilian reptiles and top predators, indicating critical knowledge gaps that need to be addressed and considered when selecting sentinel wildlife for ecotoxicological investigations.

Similarly, there is great need to better monitor human exposure levels to EDCs and establish how this contributes to the increasing incidences of disorders of the reproductive tract and declining fertility rate in both women and men. There is now evidence of sensitive timing of exposure, more specifically during development, which underlines the importance of identifying populations at risk from a biological point of view (i.e., pregnant women and the foetus, newborn) but also possibly in relation to socio-economic status (i.e., occupational and residential exposures). Follow-up cohorts exist in Canada to monitor mother-child health (CaMCCo Canadian Mother-Child Cohort); however, specific monitoring of the issue of EDC exposure on long-term reproductive health over one or more generations requires further investment and support. Environmental health is becoming a topic of interest to the general public, thus, there is a need to better understand the physiology of reproduction and the mechanisms by which EDCs act. This is imperative to not only find ways to counteract their negative effects, but also to better inform and educate young people and people of reproductive age of the possible effects.

reference link https://www.sciencedirect.com/science/article/pii/S0013935121018855



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