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Comprehensive Effects of Parabens in Human Physiology

Seeham Ali Qasim Alkafajy1*, and Rawaa Abdul-Ameer Abdul-Jabbar1

1. Dept of Biology, College of Science, Mutansiriyah University, Iraq

*Corresponding author: [email protected]

Abstract:-

Parabens are industrial chemicals that have been widely applied as for many products, such as , medicines and foodstuffs, due to their ability to extend the life of products and prevent pathogenic bacteria and mold from developing them. Paraben compounds include , , , , heptylparaben and benzyl-paraben.P-hydroxybenzoic acid is the main receptor of parabens in the human body, recently, it has been observed these compounds are present in blood serum and urine in different concentrations after multiple and long-term exposure to parabens as it is absorbed through the skin due to the ability of parabens to dissolve in water. Also, the increased ability of parabens to penetrate the skin depends on their structures, length of side chains, and the type of volatile solvents such as acetone and . Academic studies have also proven the presence of these chemical compounds in the breast tissue of breast patients, as the estrogenic properties of parabens may play a role in the development of that has raised public concern about their use. Other studies have confirmed that parabens are classified among substances that cause endocrine function disruption, such as the thyroid and adrenal glands. On the other hand, researches indicated that women who have a high concentration of polyethylene paraben suffer from short menstrual periods and poor fertility, and current studies conducted on male rats have found that parabens negatively affect the function of the male reproductive system by reducing the concentration of sperm, reducing the level of secretion in their serum and comprehensively affects the quality of semen in males.

Keywords: Parabens, human physiology, industrial chemicals

How to cite this article: Alkafajy SAQ, Abdul-Jabbar RAA (2020): Comprehensive effects of parabens inhuman physiology, Ann Trop Med & Public Health; 23(S20): SP232242. DOI: http://doi.org/10.36295/ASRO.2020.232242

Introduction

Parabens are compounds in processed foods, , , topical/parenteral pharmaceuticals pharmaceutical products and cosmetics utilized to inhibit the growth of , hence, extending the life of products having these chemicals. On the other hand, chemically are defined as a family of chemicals that are series of alkyl or salts of para-hydroxybenzoic acid (PHBA) that Annals of Tropical Medicine & Public Health http://doi.org/10.36295/ASRO.2020.232242

occurs naturally in many vegetables and fruits, like blueberries, cherries, onions and carrots, also naturally formed in the human body by the breakdown of some amino acids, etc (1,2) .

As a result of high exposure to large amounts of Parabens, the human body quickly changes Parabens into natural PHBA and eliminates them, and this is confirmed by many studies that indicate that large percentage of it has been removed by urination within 24 hours(3, 4,5), Abbas and his colleagues in 2010 confirmed that in their study (6), it has no effect on the liver, but it could be detected in human plasma (4), milk (7) urine (3), and seminal (4), bio monitoring data could help scientists to determine who been exposed to higher levels of parabens depending on age, sex, and race (8,9). This substance has numerous beneficial characteristics such as resistance to hydrolysis, chemical stability within a wide range of pH and temperature, high water solubility, low frequency of sensitization or irritation, low production cost (10).

Physico - Chemical characters of parabens :-

Parabens are group of esters of para-hydroxybenzoic acid figure (1), the R symbol is represented an alkyl group such as ethyl, propyl, methyl, butyl, and heptyl which are known as ethylparaben (E214), propylparaben (E216), methylparaben (E218), heptylparaben (E209) and butylparaben respectively (11), the alkyl group ( alkyl chains) differ only in the length and branching, depending on these characteristics, however its solubility in water and log Kow (lipophilicity) will change between the types of paraben, is based on the length of the carbon chain of the alkyl group figure 1, researcher found increasing of the carbon chain cause decreasing water solubility, raising log Kow (lipophilicity), and boosting antimicrobial activity (12).

Figure 1 General chemical structure of Parabens

These substances differ in their Physicochemical characteristics such as molecular weight, melting point, boiling point, pKa, the ability to solube in water in different temperatures and the ability to solube in ethanol, are presented in Table 1 (10, 13, 14).

Annals of Tropical Medicine & Public Health http://doi.org/10.36295/ASRO.2020.232242

Table 1 Physicochemical characteristic of the common paraben types. type ethylparaben propylparaben methylparaben heptylparaben butylparaben Particular weight 166.17g/mol 180.2 g/mol 152.15 g/mol 236.307g/mol 194.23g/mol melting point 116 °C 97.0 °C 131°C 49-51°C 68-69 °C boiling point 297-298 °C 294 - 295 °C 270-280°C 338.77°C - pKa 8.22 8.35 8.4 8.5 8.37 solubility in water 0.17 0.05 0.25 mg/L 0.02 mg/ml 0.02 at 25 °C, g/100 mL solubility in water 0.86 0.30 2.00 - 0.15 at 80 °C, g/100 mL solubility in ethanol 41 50 32 - 68

In general, Paraben types are hygroscopic crystals or powders have no taste, smell or colour and for these properties are used in the food and cosmetic industry because it does not change the nature of the product in terms of colour, taste, aroma and density (14, 10).

Biosynthesis of parabens:-

Parabens are an organic chemical which can be acquired naturally and synthetically, naturally produced by the esterification of para-hydroxybenzoic acid (15, 16) , that exists naturally in many plants (such as cherries, cucumbers, carrots, onions, Japanese honeysuckle, cocoa, vanilla, strawberries and blueberries), microorganisms (such as microbulbifer bacterium) and also formed in the human body by the breakdown of some amino acids (17), while industrially produced by the esterification of para-hydroxybenzoic acid with analogical (18) as in the chemical equation below

C7H6O3 + ROH= C7H5O3R + H2O

The symbol R represents CH3, C2H5, C3H7, C4H9, and this chemical formula C7H5O3R represent methylparaben, ethylparaben, propylparaben, butylparaben respectively (18), and know new manufacture technologies to save cost and energy during the manufacturing process of parabens by utilizing catalysts as microwave radiation and inorganic salts.

Metabolism of parabens in human body

Parabens as they’re widely used nowadays in food, cosmetics, and health products including drugs, there is an increased percentage of the potential side effects due to exposure of our bodies to large amount these substances. Its’ bioavailability is seen less in petrolatum preparation and much more in oil-in-water ones. The absorption is mainly percutaneous and it’s changeable according to the used surfactants. The parabens’ absorption is also affected by the oil/water phases of the formulation. Mostly all parabens consider are Annals of Tropical Medicine & Public Health http://doi.org/10.36295/ASRO.2020.232242

hydro- or lipophilicity, and have stability over a large pH range, (19) as many studies that confirmed that parabens compound are rapidly absorbed, metabolized and excreted from the body, 70% by urination, 4% by faeces, 2%were retained in the tissues and carcasses(20), but it cannot fully metabolize, and Aubert and his colleagues in 2012 added that all administration routes (oral, topical or subcutaneous administration) could enter the systemic circulation and give a single peak in the plasma and not accumulated in the tissues (20), but another study has proven that there is an accumulation of this substance in the different types of tissue such as brains, umbilical cords, and uteri (21), also study done by Xue and his colleagues in 2015 included marine creature include polar bears from the Chuckchi Sea and the Beaufort Sea found that trace concentrations of methylparaben in their livers (22,23), and Xue and Kannan in 2016 study also found trace concentrations of methylparaben in the tissues of albatrosses in Northwestern Pacific Ocean in Midway Atoll (24), parabens hydrolyzed into para-hydroxybenzoic acid (PHBA) and , in the liver, microsomes, small intestine, and in the skin of the mammals by esterases enzymes(21), and finally excreted as sulfate, glycine, and glucuronide conjugates by urination (23), and Kang and his colleagues in 2016 (5), explained that the concentration of parabens residues in urine differs between different populations and these differences due to the applicable laws of the countries regarding the maximal permissible concentration of parabens in the products.

Health implications of parabens:-

Parabens are found in a variety of products, have also been detected in urine and blood samples in the different populations, and concerns have been raised it can affect human health, over the last years, parabens have become huge buzzwords in the beauty, although individual products may contain limited amounts of parabens within safe limits set by the U.S. Food & Drug Administration (FDA), however, there’s a chance that parabens products harmful due to cumulative exposure of this substance, may cause a wide range of health problems, and for this must avoid them like the plague and COVID 19.Nowadays, there is a concern about using parabens as it safe or not as these compounds have been shown harmful effects on hormonal function and human health.

1- Effects of parabens on the skin

Parabens are the most common synthetic preservatives, and the excessive using of parabens cause unfavorable health outcomes (10), so may induce allergic contact with a serious type of skin inflammation characterized by rashes, blisters, and burning skin (25) and parabens have estrogenic activity which inhibits sulfotransferase in human skin, due to its ability to soluble in water, so it could easily absorb and penetrate the skin which influences skin retention (26) whereas the ability of parabens varies in penetration the skin depending on structures and the length of the ester side chains and using the volatile solvents acetone and ethanol which increase its ability to the penetration (26, 27), and then reaching to the bloodstream , researchers found that parabens in the human tissues (breast tissues, liver) and fluids (blood breast milk, serum, seminal fluid and urine) (28) , British study was done by Darbre and his colleagues in 2004 detected traces of five parabens which unaltered by the body’s metabolism, in the breast tumours of 19 out of 20 women studied, that indicate that parabens could penetrate the skin and remain in breast tissue which increasing incidence of breast cancer due to the use of underarm containing parabens (29) there are factors with parabens that effects on the skin health (30), these factors include exogenous factors (chemicals, UV radiation, ionizing radiation) and endogenous factors (hormones, metabolic processes, genetic predispositions) which cause functional and structural changes in the skin, Annals of Tropical Medicine & Public Health http://doi.org/10.36295/ASRO.2020.232242

such as UV exposure of sunlight which causes increasing of skin cancer (31) , and many studies have proven the presence of parabens in the urine people who use parabens-containing cosmetics, and this gives an indication of its easily absorption through the skin and its access to the urine (32), which over time could cause harm, and Aubert and his colleagues in 2012 found the all routes of parabens administration produced a single peak in the plasma of para-hydroxybenzoic acid (PHBA)( 20), and many studies found that the concentration of parabens in the skin, urine, milk, and blood increased with the frequency and quantity of using cosmetic products and exposure to parabens also occur through ingestion and inhalation(3,4,7, 33).

2-Effect on menstrual period:-

Japanese research indicated the shortened length of a menstrual period in ladies with a high concentration of urinary parabens, this study recommended that the parabens may be one of the environmental reproductive problems (34)

Another study by Jiménez-Díaz and his colleagues in 2016 found in their research through investigation for four parabens types (methyl-, ethyl-, propyl- and butylparaben) in the Spanish women menstrual blood samples and they found that there were concentrations of parabens types and the most frequent detected compounds was methylparaben (35) .

Further studies will be needed to confirm the link between parabens and menstrual period length, and the concentrations of parabens in women menstrual blood samples.

3-Disrupting Endocrine Compounds:-

The endocrine system is a collection of glands that produce hormones to organize biological events like growth, metabolism, development, reproduction and etc, therefore it consists of the pituitary gland, pancreas, thyroid gland, parathyroid glands, adrenal glands, ovaries and testicles. Hormones are known as signaling molecules transported by the circulation system to the goal places.

The disorders of hormonal functions may be caused many factors, the substances like parabens considered an exogenous factor that change functions of the endocrine system and alternately the damage will occur in the health (36). Recently it was found that parabens disrupt hormones function through to interfere with normal hormone functions on various levels, an effect that is linked to increased risk of the different diseases linked with the different hormones, such as obesity, cancer, allergic diseases and etc. (37,38 ) this is due to the presence of the parabens in blood and tissues samples as a result of the accumulation of paraben in this tissues, and Nowak and his colleagues in 2018 in their review say further studies are necessary to find out how parabens affect human health (39). There are many research found a correlation between the presence of parabens in the breast tissue due to the uses of deodorant products under the arms which were close to the breast and thus will cause the development of breast cancer (40 ) There are many studies that declare the reassessment of parabens risk through understanding the relationship between the use of parabens and health state of the parabens users or the experiments that use animal models(34), many scientists investigated the effects of parabens on the functioning of internal organs by the use of animal models to evaluate the general effects in weight and histopathology of the

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internal organs (35) but Lemini and his colleagues in 2003 and Nowak and his colleagues in 2018 indicate that the effects of parabens which observed in animals experiment not concur with human studies (41, 39).

The Zhang and his colleagues study in 2014 suggest the exposure to butylparaben during pregnancy and lactation has pernicious effects on the reproductive system in rats off spring of males and increase of (E2) levels which the author consider this case as biomarkers for endocrine-disrupting(42), while Vo and his worker in 2010 found by using a female rats model that treated with different types of parabens (including butyl-, ethyl-, methyl-, propyl-, isopropyl-, and isobutyl-paraben) significant weight changes in the body and organs (adrenal glands, liver, ovaries, thyroid glands, and kidneys)(43), but no significant histopathological changes were observed in the adrenal and thyroid glands and significant histopathological abnormities in the reproductive organs and also found a significant decrease in serum thyroxine and estradiol concentrations (44), while Taxvig and his colleagues in 2008 found that butylparaben acts as an through interfering with cholesterol transport to the mitochondrion which leads to interfering with steroidogenesis (45).Estrogen hormones are considered the target action for parabens as these chemicals are easily absorbed by the skin when applied as cosmetics formula (39).

Parabens are called estrogen-mimickers which gives it the property of hormone-disrupting like many studies that have pointed to this fact and for this reason, it is ranked by the United Nations Environment Programe as endocrine-disrupting chemicals (EDCs), which can affect estrogen receptors by forming ligands to the plasma proteins, causing the disruption of the peripheral activity of the circulated hormones. In addition, EDCs weaken the activity of enzymes that metabolize endogenic hormones, like aromatase, 5- reductase and 3-HSD. Further, EDs are able to impair the synthesis and biotransformation of non- bioidentical hormones (46).

There are many studies interested in the effect of parabens on thyroid hormone levels during pregnancy because it’s a sensitive period with a lot of hormone changes, parabens associated with the decrease in FT3 and increase in FT4 but not significantly associated with TSH in pregnant women (47) while another study by the same researcher in 2019 showed a general TSH decrease in association with parabens, and decrease in T3/T4 ratio, as well as T3(48), and other studies found no associations between parabens and thyroid hormones as (49). The increasing of cause increase T4-binding globulin (TBG) that lead to increases in total T4 levels which cause endocrine disruption and due to the estrogen-like effect of parabens, it acts through to simulate a hormone or imitates the hormone and cause block the receptors of a hormone and all these leas to disruption of the hormonal system through the effect on the estrogen- dependent genes, many studies have reported that parabens may affect thyroid function due to its estrogenic and anti‐androgenic properties and cause obesity (50), and Hu and co-workers in 2013 (51) reported that parabens modulate adiponectin, adipokines and leptin through it adipogenic effect to converse adipose tissue to stromal cells, and Berger and co-workers in 2018 found that parabens associated with lower free T4 and TSH in pregnant women(50,51).

Effects of human fertility:-

As many studies indicate that estrogenic activity of parabens increases with the length and branching of the alkyl chain and act as antiandrogens and may affect thyroid function and all of these factors have a role in the fertility (52, 53,32,43), and many studies in animals and human beings suggested that parabens have mimicked the hormone estrogen and lower testosterone levels, (54,23, 55 A, 55 B,), Jurewicz and his colleagues reported in 2020 that men who have been exposed to parabens have lower testosterone levels and more of abnormal sperm, and the increasing of parabens concentrations in the urine associated significantly with an increase in the percentage of abnormal shape sperm and slow-moving(56), the

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estrogen-like effect of parabens may also cause hormonal changes and the cause of many diseases such as cardiovascular disease, breast cancer, obesity, cancer, allergic diseases and etc (38). so they classified parabens as endocrine disruptors due to its estrogenic effects (57)

There are many studies that simulate the effects of parabens on health in various aspects, where have a weak estrogen-like effect which may disrupt natural estrogen, through binding with (ER)- alpha and (ER)-beta, so it alters the physiology of the reproductive system as we see in Japanese study on the effects of parabens on the reproductive system, the study the effects of parabens on the length of menstruation in women over the period for 5 months who exposure to slightly parabens products and they found that negative significant relationship between the length of menstruation and urinary total paraben and these results suggest that parabens may cause problems in the human reproductive (34), and Spanish study by Jiménez-Díaz and his colleagues 2016 found in the women menstrual blood samples concentrations of parabens types (methyl-, ethyl-, propyl- and butylparaben) and the most frequently detected compounds were methylparaben (35), while in the study performed by Jurewicz and co-workers in 2020 emphasized in their research on the contribution of parabens to reduced fecundity and impair fertility female(56), as there is an inverse association between urinary concentrations of parabens and decrease antral follicle count (AFC) and decrease estradiol (E2) level and positively associated with stimulating hormone (FSH), while Pollack and his colleagues in 2018 indicated that parabens lead to an increase in the estradiol levels(58). Studies on the males, represented by the study of Oishi in 2002 conducted on male rats found that parabens negatively effect on the function of the male reproductive system by decreasing the concentration of sperm and decreasing the level of testosterone secretion in their serum and another study about the effect of parabens on semen quality in males(59), they didn't find any negative significant effects of parabens use and attribute that to the little using of parabens by men in addition to the small sample size (34). Studies revealed parabens could interfering with thyroid hormone and , and disrupting the endocrine system through disrupting the previously mentioned hormones (60). Taxvig et al 2008 demonstrated that butylparaben act as an endocrine disruptor by interfering with the transport of cholesterol to the mitochondrion and interfere with steroidogenesis(45), and butyl and Propylparaben cause a reduction in testosterone levels and sperm production in rats (59) while Kang et al 2002 demonstrated that pregnant and lactating women whose parabens containing products will affect on the organs of the reproductive system and sperm count of the offspring(61), and Frederiksen and his colleagues 2008 found parabens in plasma and amniotic fluids of pregnant women also, they found the female fetuses more sensitive to the parabens than the male fetuses(62), and these compounds have additive effects (45), and the possible explanation for this that parabens disrupt maternal hormones and placental secretion in the fetal sex-specific way(60). Many studies found that parabens higher in females than in males (5,63) Further studies need to be done in order to determine parabens exposure safety, and further studies need to determine the relation between parabens types as an environmental pollutants and different diseases.

Conclusion:-

Paraben types used as preservative substances in different types of pharmaceutical, cosmetics and food products, and although studies have conflicted about parabens effect on the human health there are many studies have proven the presence of parabens in different types of human samples such as tissues and different bodily fluids and found that mimic the estrogen hormone in its effects on the different types of the organ in the human body, and recently found decreasing use paraben products led to a reduction in their concentration in the body, therefore, special attention must be paid to the real risks posed by the continued use of products containing paraben types as a preservative. Annals of Tropical Medicine & Public Health http://doi.org/10.36295/ASRO.2020.232242

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