The Effects of Environmental Pollutants and Exposures on Hair Follicle Pathophysiology Free

Anthropogenic environmental contamination can have profound and devastating impacts on human health. Skin is uniquely positioned as the primary barrier and first line of defense against the exposome. Increased recognition of the effects of environmental contaminants on cutaneous health has contributed to the growing field of environmental dermatology. Pollution has been linked to many dermatologic conditions, including atopic dermatitis, psoriasis, skin aging, and acne [1, 2].

Within the skin, hair follicles (HFs) are especially vulnerable to environmental pollutants. Matrix keratinocytes rank among the most proliferative of mammalian tissues and are highly perfused, thus receiving exceptional exposure to pollutants via the bloodstream [3, 4]. Some small molecules are capable of absorption through the stratum corneum and even directly via the HF orifice [5‒8]. Certain pollutants may therefore penetrate HFs through transfollicular and transdermal exposure routes, affecting all functions of the follicular unit, including sebaceous excretion (Fig. 1) [9].

Hair shaft production is an excretory activity, and it is well known that hair can reveal past exposure to recreational and pharmaceutical drugs. It is even hypothesized that toxin excretion may be a key evolutionary function of hair [10]. Furthermore, HFs are sensitive to environmental stimulation, harboring gustatory, olfactory, and photosensitive receptors [11, 12]. These receptors possibly respond to changes in the HF microbiome, as dysbiosis is associated with many HF pathologies [13]. HFs are also hormone sensitive, providing a possible mechanism by which endocrine-disruptive pollutants might impact their function [14].

Thus, a question is raised: what impacts are increasing levels of environmental contaminants in air, food, and water having on HF pathology [10]? Despite the biological plausibility that environmental pollutants would impact hair, research into this topic is limited. Here, we review the literature regarding the impacts of several key exposures on HFs and highlight gaps in the current research.

The association between particulate matter (PM) and poor health outcomes, such as COPD, hypertension, cancer, Alzheimer’s, and other diseases, has been well established. However, their dermatological impacts, particularly on the hair, have not been as well elucidated. Climate change has increased the frequency and intensity of pollen seasons, wildfires, tornadoes, and other natural disasters, all of which can increase the level of small particulate pollutants [15, 16]. PM_2.5 (particulate matter ≤2.5 μm in diameter) and PM₁₀ (particulate matter ≤10 μm in diameter) may contain dust, pollen, mold, smoke particles, combustion waste, and more. PM can enter the body through both transcutaneous absorption and inhalation.

In previous dermatological studies, PM has been linked to the worsening of dermatological conditions such as pemphigus vulgaris and atopic dermatitis [17]. Less research regarding PM and hair health has been conducted. Billions of PM can be deposited on hair surfaces for those living in highly polluted environments [18, 19]. This leads to hair surface changes such as loss of shine and structural alteration due to the frictional force of PM on the follicle [18].

Beyond cosmetic changes, some studies associate PM exposure with clinical conditions such as alopecia areata [20]. Epidemiologic analysis has also demonstrated that incidence of alopecia areata is significantly higher in urban, industrialized areas compared to rural regions [21]. Research using ex vivo follicular keratinocytes has shown that PM exposure induces apoptosis in the HFs [9]. It is hypothesized that PM_2.5 may increase C-reactive protein, fibrinogen, and leukocytosis [19]. In zebrafish embryos, the addition of PM_2.5 significantly reduced the number of hair cells in neuromasts in a dose-dependent manner [22]. In this study, staining showed increased mitochondrial damage in embryos exposed to PM_2.5, potentially secondary to neuroinflammation [22]. Therefore, it is possible to extrapolate that PM deposition onto the hair can cause local damage to the hair shaft, while systemic exposure via transcutaneous absorption and inhalation can result in inflammatory damage to the HF, leading to follicle damage and hair loss.

Tobacco smoke is composed of over 4,700 chemicals, many of which are known to be hazardous and carcinogenic [23]. Second-hand smoke refers to smoke that is exhaled or emitted from burning tobacco before mixing with ambient air, while third-hand smoke describes gases and particles from smoke that linger for long periods of time in dust, fabrics, and surfaces [23, 24]. The detrimental consequences of second-hand and third-hand smoke exposure for cardiovascular and respiratory health are well established, resulting in an estimated 1.3 million premature deaths annually [25, 26]. Moreover, the global morbidity and mortality of environmental tobacco exposure is uptrending [23, 27].

Passive smoke exposure is often measured using levels of nicotine or its metabolites, such as cotinine, in hair shafts. These levels reflect the average concentration of nicotine in the blood over long periods of time, which in turn reflects the quantity that has been inhaled or ingested [23, 28‒30]. Nicotine is believed to pass from blood vessels in the dermal papilla into the growing hair shaft via passive diffusion [31]. In the past, some have argued that nicotine is primarily adsorbed into the shaft from surrounding air, which would suggest fewer implications for follicular pathophysiology. However, this is now believed to be a secondary, smaller contributor to overall hair shaft nicotine levels and is controlled for in the laboratory setting by simply washing the hair before analysis [32].

Follicular damage from tobacco smoke is multifactorial and includes vasoconstriction of the cutaneous microvasculature, increased cellular senescence, and hormonal changes including estradiol hydroxylation, aromatase inhibition, and increased androgen levels [31]. Tobacco smoke also yields reactive oxygen species formation, resulting in DNA damage and increased apoptosis. One in vivo study in rats seeking to characterize smoking-induced damage to skin and skin appendages observed HF reduction and degradation [31, 33]. Given the massive and growing scale of passive smoke exposure globally, further investigation into the specific effects of tobacco smoke on HF function is needed.

Polyaromatic hydrocarbons (PAHs) are a heterogeneous group of hundreds of compounds that occur naturally in fossil fuels and can be produced by the burning of organic material. Humans are exposed via cigarette smoke, roasted or burnt food, polluted air, and via skin exposure to contaminated soil and water [34‒38]. Some PAHs, like benzo(a)pyrene, are potent carcinogens [35, 39]. PAHs are known ligands of the aryl hydrocarbon receptor. In the skin, this receptor plays a critical role in epidermal differentiation and barrier function and has been a pharmaceutical target for treatment of psoriasis and atopic dermatitis [40‒43]. PAHs have been implicated in extrinsic skin aging, pigmentary disruption, and dysbiosis [44‒47].

HFs also express aryl hydrocarbon receptors and therefore are likely vulnerable to environmental PAHs. One study investigating the pathophysiology of androgenetic alopecia found overexpression of nuclear aryl hydrocarbon receptors in the keratinocytes of miniaturized follicles. The authors hypothesized that aryl hydrocarbon receptor stimulation promotes apoptosis via the Fas and TNF-related apoptosis-inducing ligand (TRAIL) pathways, thus promoting follicular regression and miniaturization [48]. Other studies have implicated these receptors in HF regeneration and cycling [49]. It is thus likely that PAHs have other impacts on HF physiology that remain incompletely characterized.

Though not a pollutant, ultraviolet (UV) light is an environmental exposure directly impacted by anthropogenic activities. The atmospheric ozone layer, which absorbs most of the ultraviolet radiation (UVR) emitted by the sun, suffered significant depletion in the second half of the 20th century due to human production of organohalogens and other free-radical-producing compounds. Thanks to international regulatory efforts, the ozone layer is gradually healing, though present ozone levels globally are still below those of the 1970s [50, 51].

Increased UV exposure is widely recognized as dermatologically relevant due to increased risk of skin cancer. However, UVR has long been understood to also affect hair. Most current research focuses on the effects of UVR on hair shafts. UV exposure causes oxidation of lipids, triggering dramatic changes in the hair shaft lipidome and decreases in most lipid classes, and also results in oxidative protein modification [52, 53]. This free radical generation is amplified when the hair shaft is wet [54].

Though such UVR-induced hair shaft changes are cosmetically relevant, it is worth further exploration of the impacts on HFs themselves. UVA is capable of penetrating the deep dermis. While UVB reaches only the upper dermis, it is still known to dramatically affect dermal physiology – for example, by influencing epidermal expression of matrix metalloproteinases, which then diffuse into the dermis [55, 56]. Thus, it is only logical that UVR will also impact the dermal follicular unit.

UVR, especially narrowband UVB, has been shown to stimulate differentiation and migration of melanocytes from HF neural crest stem cells, both in vitro and in murine models in vivo. UVR also stimulates increased dendricity and tyrosinase and melanocortin-1 expression in differentiated HF melanocytes. Melanocyte stem cell stimulation in the HF is thought to represent the major mode by which epidermal melanocyte quantities increase following UVR [57‒59]. HFs also serve as reservoirs for Langerhans cells that can repopulate the epidermis after UVB exposure [60].

Perhaps the most comprehensive study of UVR on HFs was done by Gherardini et al., who applied trans-epidermal UVA and UVB radiation to ex vivo human HFs in scalp skin. The UVR induced oxidative DNA damage and cytotoxicity, increasing apoptosis and decreasing proliferation in both the outer root sheath and the matrix keratinocytes. UVR also induced catagen, altered HF growth factor expression, and triggered perifollicular mast cell degranulation [61].

The method by which UVR impacts HF physiology is an active area of research. Anagen HFs are known to express photoreceptors including OPN2 (rhodopsin) and OPN3 (panopsin, ecephalopsin), the stimulation of which influences hair shaft growth [62]. Other hypotheses include that UVR induces photoactivation of porphyrins produced by Propionibacterium sp. in the pilosebaceous duct and direct oxidative damage to HF keratinocytes, resulting in microinflammation [63].

While there are multiple heavy metal contaminants, this article will predominately discuss thallium, mercury, and selenium. These elements have been implicated in hair pathologies, particularly in cases of alopecia areata [64‒66]. While the skin is a significant route of absorption for heavy metals, their primary symptoms of toxicity manifest in other systems including neurological, pulmonary, renal, or reproductive organs [67‒69]. Heavy metals have oxidative properties that can cause DNA mutations through base modification, cross-linking, scission, and depurination and through these processes lead to toxicity or carcinogenesis [70].

Thallium is a soft, water-soluble metal with no color, odor, or taste. It is found naturally on Earth and has been used for industrial and criminal purposes. Currently, thallium is used in the semiconductor, optical, and pesticide industries. A thallium level of 10–15 mg/m³ is considered acutely lethal for humans. Therefore, it has an occupational limit of 0.1 mg/m³ for 8 h [71]. Thallium can be absorbed through the skin or via inhalation. Exposure is predominately occupational, although exposure through contaminated products or intentional poisoning has been reported. Symptoms of poisoning include gastrointestinal distress, neurological symptoms, and ocular symptoms [71]. Dermatological effects have been described as scaling and acneiform eruptions, followed by alopecia and Mees lines on the nails. Thallium-associated alopecia tends to appear 2–3 weeks after exposure [71].

In the past, thallium acetate was used for dermatophytosis such as tinea capitis, with case reports from as early as 1928 noting depilation as a side effect of this treatment [72, 73]. Recent case reports continue to note the association of thallium exposure to alopecia of the scalp, eyebrows, and even body [74, 75]. The pathophysiology of thallium toxicity is through its structural similarity to potassium. On a cellular level, thallium can disrupt potassium-dependent processes, leading to decreased ATP production [71]. However, its hair-related toxicity is due to its affinity for disulfide bonds. Thallium binds to cysteine residues, disrupting cross-linking and leading to a decreased amount of keratin formation [71]. Decreased keratin formation, in addition to decreased ATP production in the metabolically active hair sites, may be attributed to the finding of alopecia in acute and chronic thallium poisoning [71].

Mercury is a shiny, silver-white metal that is liquid at standard temperature and pressure. It has been used in medicinal and industrial products for centuries and therefore has become a common environmental pollutant. Mercury comes in organic, inorganic, and elemental forms.

Exposure to organic mercury often occurs through ingestion of contaminated seafood products or encounters with mercury-containing paints. Methylmercury is an organic form of mercury that often bioaccumulates in large predatory fish like sharks, swordfish, or tuna [76]. Methylmercury is known to accumulate in HFs during the hair growth stage, where concentrations are proportional to blood concentrations [76]. Therefore, hair has often been used in biomonitoring of methylmercury exposure. Inorganic or elemental mercury is found in thermometers, batteries, or laxatives. In general, organic mercury has a longer half-life than inorganic mercury and is excreted fecally, whereas inorganic mercury is predominately excreted renally [67]. Symptoms of mercury poisoning include abdominal pain, renal dysfunction, and neurological symptoms such as orofacial paresthesias, tremors, ataxia, or dementia [67].

Dermatologically, mercury poisoning is correlated to graying of the oral mucosa [67]. However, heavy metals like mercury have been associated with alopecia [64, 66, 77]. In the hair, nearly 90% of the mercury found is in the organic methylmercury form. However, all forms of mercury have the potential to induce alopecia [66]. Like thallium, mercury can bind to sulfhydryl groups in keratin and cause anagen effluvium [64]. Not only is there structural change to keratin, but mercury can cause metabolic toxicity by also binding to amide, carboxyl, and phosphoryl groups to cause enzyme, membrane, and structural protein damage [67]. Mercury independently can cause oxidative damage in addition to dysfunction [67]. The level of toxicity needed to induce alopecia is not known; however, it is important to consider mercury toxicity in patients presenting with alopecia accompanied by neurological symptoms.

Selenium is a mineral found naturally in water, soil, and certain foods. It is an essential micronutrient and component of selenoproteins, which serve an important role in hormone production [78]. Selenium exposure typically occurs via dietary intake. Selenium exists in high concentrations with certain foods such as paradise nuts or Brazil nuts, or dietary supplements [64]. Elemental selenium is relatively nontoxic; however, in selenite or selenate form it has a low threshold for toxicity, with the LD₅₀ in various mammal studies ranging from 1.5 to 3.0 mg/kg [79]. The recommended dietary allowance for humans is 55–70 μg daily. Selenium is excreted renally at a rate of 13 μg/g creatinine for women and 10 μg/g creatinine for men [80].

Selenium poisoning often resembles heavy metal poisoning, even though selenium is a nonmetal element [64]. Patients with selenosis often present with vague symptoms such as nausea, diarrhea, dizziness, myalgia, and fatigue, beginning a few hours after ingestion. Selenosis more commonly has dermatological symptoms such as dermatitis as well as hair and nail pathologies, which occur a few weeks after exposure to high levels of selenium [64]. In a study of 73 individuals who were exposed to excess selenium in a mis-formulated supplement, 77% had fingernail loss while 92% lost scalp or body hair [81]. It is hypothesized that selenium substitutes sulfur in keratin protein, breaking disulfide bridges and leading to structural hair and nail abnormalities [64]. Studies show most cases of dermatological symptoms from selenosis are reversible, although there are some instances of long-term damage [79].

The breakdown products of plastic materials include microplastics (<5 mm) and nanoplastics (<1 µm), which form a heterogeneous group of contaminants with diverse shapes, sizes, compositions, and origins. These ubiquitous pollutants can cross epithelia and enter the body via ingestion, inhalation, or cutaneous contact. However, the ramifications of lifetime exposure and accumulation of these particles are poorly understood [82, 83].

Microplastics are dermatologically relevant as particles smaller than 1 μm can penetrate the stratum corneum of healthy skin [84‒87]. Larger particles can penetrate in cases of damage to the stratum corneum, as is seen in atopic dermatitis [84, 88]. One study using fluorescent micro- and nanoplastics revealed that the particles can be directly taken up by mouse keratinocytes and fibroblasts in vitro, resulting in both nuclear and cytoplasmic bioaccumulation [84]. This uptake was linked to increased intracellular levels of reactive oxygen species, activated Nrf2 stress signaling, and elevated markers of apoptosis and DNA damage. Furthermore, microplastic bioaccumulation resulted in modulation of cytokine expression and β-catenin signaling [84]. The “epithelial barrier hypothesis” posits yet another possible route of microplastic-induced cutaneous disruption. This hypothesis argues that by compromising barrier integrity and triggering epithelial inflammation, pollutants – including microplastics – induce microbial dysbiosis and bacterial translocation [89‒91].

Currently, there are no studies directly testing the impacts of microplastic exposure on HF physiology. However, several studies have demonstrated that microplastics are present at measurable levels within the hair shaft [92, 93]. Moreover, the cellular pathways previously demonstrated to be affected in primary skin cells, like the Wnt/beta-catenin pathway, are known to be critical in HF growth and development [94]. Dysbiosis is known to be associated with key follicular pathologies, from common conditions like acne vulgaris to severe cicatricial alopecias like folliculitis decalvans [13]. It is therefore plausible that microplastic exposure – through ingestion, inhalation, or direct external contact – may have clinically relevant impacts on follicular disorders. More research into this area is warranted.

Phthalates are ubiquitous esters of phthalic acid used as plasticizers. Humans are exposed via contaminated food and water, leachate from packaging, PM containing microplastics, and cosmetic products [95, 96]. Phthalates are known to cause systemic endocrine disruption, even impacting fetal development and pubertal timing, by mimicking estrogen [97‒102]. Exposure to phthalates is often measured using hair shaft levels, indicating that HFs receive significant exposure to these chemicals [103, 104].

HFs are known to be hormonally sensitive, expressing estrogen and androgen receptors, and producing key enzymes like aromatase and 5-alpha reductase [14, 105]. Several hair pathologies, such as androgenetic alopecia, are influenced by systemic hormone levels. No association between phthalate exposure and alopecia has yet been reported, but more research is warranted.

Pesticides are chemical substances used to control unwanted organisms, particularly in agricultural settings. Annually, there are over 1 billion pounds of 500 different types of pesticides in use in the USA [106]. While pesticides work by poisoning specific aspects of the pest’s biological system, they have also been found to have harmful effects on humans. Pesticide exposure occurs predominantly through transcutaneous absorption [107]. Inhalation or ingestion are also forms of exposure. Toxic effects of pesticide exposure can include mild symptoms such as skin irritation, headache, and nausea to more severe symptoms such as convulsions, coma, or death [108].

In many biomonitoring studies, pesticide exposure has been accurately tracked through hair concentrations [109‒120]. The ability to track pesticide residue in hair shafts indicates that pesticides may have significant accumulation in the HF. However, the impact of pesticides on follicular health has not been well elucidated. One review linked the insecticide boric acid with anagen effluvium, alopecia totalis, and eyelash loss [64]. A 1973 case report noted toxic alopecia from chronic ingestion of boric acid, which was previously used as a component of mouthwash [121]. The authors also hypothesized that boric acid may have been collected in the HFs. In a separate case series, 3 patients noted patchy or global alopecia after occupational exposure to boric acid-containing products [73]. The connecting factor between these three cases was that the boric acid was suspended in a solution, and alopecia occurred in regions where this solution touched hair-bearing skin. All cases of toxic alopecia reversed after discontinuation of boric acid exposure.

The mechanism of action of pesticide-induced alopecia is still unknown. A study conducted on the children of farmworkers showed a significant association between the amount of pesticides exposure and DNA damage in the papillary region of plucked hairs [122]. Therefore, it is likely that pesticide-related hair pathology is due to direct toxicity or injury at the level of the HF. More research into the mechanisms underlying pesticide-induced alopecia and wider adoption of protective gear to limit cutaneous exposure is needed.

As described here, several key pollutants are found at measurable levels in the hair shaft, likely concentrated there due to hair growth being an excretory process. The methods by which these particles end up in the HF include ingestion, inhalation, and transcutaneous absorption. There are many mechanisms by which these exposures affect HF physiology, which include triggering inflammation, disrupting key signaling pathways, inducing dysbiosis, causing systemic endocrine fluctuations, triggering vasoconstriction of the papillary microvasculature, inflicting direct cytotoxicity, and binding to cellular receptors. Several studies have already connected pollutant exposure to follicular pathologies, including alopecia areata, anagen effluvium, and androgenetic alopecia. These findings are summarized in Table 1.

Given the prevalence of these environmental contaminants, further investigation into their relation to hair disorders is warranted. Though outside the scope of this review, exposures found in cosmetics and food have also been identified as culprits in HF disorders. For example, the widely used cosmetic agent linalool is a potential trigger of frontal fibrosing alopecia [123, 124]. Such exposures provide a potential point of intervention for dermatologists to counsel patients on. The far-ranging impacts pollution has on human health, including dermatology and HF pathophysiology, provide a reminder of the public health consequences of anthropogenic environmental disruption.

The authors have no conflicts of interest to declare.

No funding was received for this manuscript.

Idea conceptualization and writing (critical revisions and editing): Tara Samra, Andrea Maderal, and Rachel Lin. Writing (initial draft): Tara Samra and Rachel Lin.