Environmental contaminants,endocrine disruption,and transgender: Can “born that way” in some cases be toxicologically real?

Abstract

Gender is viewed by many as strictly binary based on a collection of body traits typical of a female or male phenotype, presence of a genotype that includes at least one copy of a Y chromosome, or ability to produce either egg or sperm cells. A growing non-binary view is that these descriptors, while compelling, may nonetheless fail to accurately capture an individual’s true gender. The position of the American Psychological Association (APA) agrees with this view and is that transgender people are a defendable and real part of the human population. The considerable diversity of transgender expression then argues against any unitary or simple explanations, however, prenatal hormone levels, genetic influences, and early and later life experiences have been suggested as playing roles in development of transgender identities. The present review considers existing and emerging toxicologic data that may also support an environmental chemical contribution to some transgender identities, and suggest the possibility of a growing nonbinary brain gender continuum in the human population.

Introduction

Initial use of “female” in this review refers to humans or animals possessing an XX genotype, while use of “male” refers to humans or animals possessing at least one Y chromosome. Use of “sex” or “sexes” implies the combination of females and males as defined by these XX and Y genotypic traits. An alternate criterium with possible case-based utility for defining “female” and “male” is then considered at the end of the review.

Endocrine disrupting environmental chemicals

Humans have synthesized multiple millions of tons of toxic chemicals and then distributed these onto the surface of the land, for control of insects, weeds and other life forms. Classes of these chemicals have included persistent organochlorines, mercury- and arsenic-based compounds, organophosphates, carbamates, pyrethroids, and diverse others. Some of these agents have been in existence for well over 100 years, for instance, the organochlorine insecticide dichlorodiphenyltrichloroethane (DDT) was first synthesized in 1884. ¹ In addition to being nearly colorless and odorless, and highly effective for killing insects, DDT also proved to be an endocrine disrupting compound, meaning it can interfere with natural hormones when it enters animal bodies. A well-known consequence of spraying large quantities of DDT into the environment for insect control was wildlife reproductive disturbance, including thinning of the eggshells of bald eagles and other carrion- and fish-eating birds. ³ Such eggshell thinning activity of DDT has been verified by studies in domestic birds including chickens, ⁴ and shown to be a consequence of disrupted prostaglandin synthesis in the uterus of the birds. ⁵

Insecticides and other chemicals like DDT wash from the land surface during rains and widely distribute via waterways. When surface soils become dry, applied chemicals are also subject to mobilization into the atmosphere with soil dusts, to be distributed by winds. The atmosphere then carries the land-applied chemicals to remote locations and redeposits them with rain or snowfall. In this manner, DDT and other pesticides and pollutants have become ubiquitously distributed, such that the entire globe is contaminated, with inhabitant life forms subject to a growing list of recognized hormone mimicking properties.^6,7 To this effect, the author has analyzed tissues of large ocean-floor dwelling crabs collected from deep waters off the east coast of the United States, beluga whales ranging north of the far north coast of Alaska, salamanders from apparently ultra-pristine mountain streams of Tennessee, marine turtles floating cold-shocked off the northeastern U.S. coast, terrestrial turtles sampled from remote United States national forest mountain sites, and numerous similar species, and has never failed to detect residues of DDT in their bodies.^8,9 Results such as these suggest that DDT would generally be detectable in human tissues as well, which is in fact the case.^10,11 Furthermore, hormonal disruption by DDT has been linked to enhanced risk of disease in humans, for instance, higher levels of DDT associating with increased incidence of breast cancer in women.^12,13 DDT, then, is only one of numerous chemicals typically detected in wildlife and humans during such analyses, with others including additional persistent organohalogen pesticides and non-pesticides. ¹⁴

A hypothesis was put forth in 1991, that widely distributed pesticides and related chemicals on the earth have the potential to subtly and broadly disrupt hormonal systems in wildlife. This hypothesis came to be known as the Endocrine-Disrupting Contaminants Hypothesis^15,16 and has been proven valid by a significant body of scientific research. Observations in wildlife have included disruption of normal estrogenic, androgenic, brain neurochemical, thyroid, and other hormone activities by these environmental chemicals.^5,17 Such hormone-mimicking or inhibiting effects of pollutants have been documented in wildlife species that include land and sea mammals, fish, amphibians, reptiles, birds, and diverse invertebrates and have been found to include changes in sex differentiation before and after birth, intersex animals that show features of both sexes, sex reversal, altered sex ratios, skewed steroid production by gonads, altered penile density, reproductive impairment, altered thyroid function, behavioral changes, shifts in brain neuroendocrine hormones, changed brain synaptic density in steroid-sensitive nuclei, and other endocrine system-related changes.^18–30

The demonstration of pollutant-induced hormone disruption in diverse wildlife species raises important questions about possible similar effects these chemicals may be having in some members of the human population. A landmark textbook published in 1996, titled Our Stolen Future, ³¹ addressed this concern by exploring ways environmental contaminants may be interfering with the hormonal control of development in both animals and humans. Chapters of this book discuss in detail how: very small changes in hormone levels during fetal development can be caused by endocrine disrupting chemicals, leading to postnatal alterations in the normal roles of estrogen and testosterone for controlling sexual development; a “single hit” of a hormone-mimicking synthetic chemical, at remarkably low levels during times of heightened programming in fetal life, can cause postnatal changes in the brain, reproductive system, and other body systems that are lifelong; very common products to which humans are routinely exposed, including plastic water bottles and plastic-lined food cans, leach and expose humans to synthetic molecules that have hormonal activity; and, the toll being taken by endocrine disruption in the human population is not clear, however, evidence from laboratory animal studies, documented changes in numerous wildlife species, and known human exposure levels suggest the human population may be at some level of risk.

Developmental origins of health and disease

Within the past 2 decades, the National Institutes of Health (NIH) has heavily funded research projects that fall under the acronym “FeBAD,” standing for “Fetal Basis of Adult Disease.” This FeBAD acronym was more recently modified to “DOHaD,” standing for “Developmental Origins of Health and Disease.” The NIH interest in funding of DOHaD research projects stems from the relatively recent realization that developmental exposure (meaning, exposure before and/or shortly after birth) to different chemicals can change early-life programming encoded by the DNA blueprint, with consequences that include increased risk of postnatal diseases, including some that manifest late in life. ³² The present author was recipient of one of these DOHaD awards, NIH R21-PAR-03-121, to examine mechanisms by which prenatal exposure to very low levels of the endocrine disrupting chemical 2,3,7,8-trachlorodibenzo-p-dioxin (dioxin; TCDD) may increase risk of postnatal autoimmune disease.^33,34 To further such interests by the NIH in contributions of peri-birth chemical exposure to later-life human health, one of the institutes of the NIH, the National Institute of Environmental Health Sciences (NIEHS), participated in launching a new scientific journal, Developmental Origins of Health and Disease (http://journals.cambridge.org/action/displayJournal?jid=DOH), where researchers can publish DOHaD-related results of their studies.^35,36

Considerable research is now available to show that developmental chemical exposures can cause persistent if not permanent postnatal changes in multiple body systems including cardiovascular, immune, respiratory, renal, nervous (brain), reproductive, and endocrine, often with overlapping effects. Researchers who focused specifically on pollutant effects in the reproductive and closely linked brain and endocrine systems of wildlife have detected changes in reproductive behavior, reproductive success, and sexual orientation. For example, developmental exposure to the widely-distributed chlorinated herbicide atrazine has been found to feminize male gonads in amphibians, reptiles, fish and mammals. ³⁷ A second, widely publicized report in white ibis birds exposed to the organometal pollutant methyl mercury at low, environmentally-relevant levels (0.05 – 0.3 parts per million in the diet), described significant changes in the normal courtship behaviors of the male birds. ³⁸ These authors concluded that pollutant-induced effects on reproductive behavior and sexual orientation in the ibis birds were the result of endocrine disruption and may represent a previously unrecognized mechanism through which chemical contaminants can impact wild bird populations.

Endocrine-related structural, neurochemical and functional differences between the human female and male brain

It is well-recognized that post-pubertal human female and male bodies on average display sex hormone-driven differences that include average height and weight, percent body fat, proportionate muscle and bone mass, pelvis width and roundness of pelvic inlet, extent and distribution of body hair, size and development of the larynx, and thickness and collagen content of skin. Early years in neuroscience research similarly identified differences in the brain portion of the human body between females and males, and viewed these as largely limited to hypothalamic-related gonadal hormone effects that underlie dimorphic sex behaviors. ³⁹ More recent neuroscience research has demonstrated microanatomic and neurochemical brain differences by sex that influence brain function at multiple and diverse levels. These differences include regional neurotransmitter levels and cortical volumes, cortical neuron and synaptic density, enzymatic pathways, regional complexity of dendritic arbors and density of dendritic spines, and locally synthesized neurohormones not regulated by gonadal hormones.^39–43 Differences such as these have been suggested to mechanistically underlie well-recognized dimorphism by sex in multiple brain neurologic diseases, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. ³⁹ The same is true for sex differences in neuropsychiatric disorders, with fewer females being diagnosed than males. ⁴⁴ Such brain differences by sex are leading some neuroscience researchers to conclude the discipline should make greater effort toward routine inclusion of sex as a factor in cognitive neuroscience evaluations.^44–46

A recent study used the National Institutes of Health Pediatric MRI Data Repository and a machine learning approach to determine if broadscale anatomic brain data can be used to correctly identify sex of individuals. ⁴⁶ These authors were able to predict sex with an accuracy of 80.4% in the 185 female and 162 male participants, aged 5–18 years. The presence of an anatomic brain sex difference was already evident at age 6 in the children studied, and increased between ages of 11 and 17, representing years associated with puberty. Brain imaging results such as these provide additional evidence of fundamental differences by sex that may contribute to neuropsychiatric differences as well as cognitive test performance differences between females and males. Females, for example, perform better on average in tasks that require verbal processing while males perform better on average in tasks that require spatial processing.^47–50 Possibly related, when brain activity was measured in females and males listening to complex tones, responses in primary and secondary auditory cortices were greater in females than males. ⁵¹ In the tasks of object shape spatial memory, differences in performance between females and males were associated with different activity levels in the parietal cortex, lateral prefrontal cortex, sensorimotor cortex, and visual processing regions of the brain. ⁵² Of clinical relevance, functional magnetic resonance imaging (fMRI) was used to show sex-specific differences in whole-brain activity between females and males related to anxiety, depression, novelty-seeking, and self-control. ⁴³ These authors joined those mentioned in the previous paragraph, in suggesting potential value of sex of patients as a factor to optimize neurologic clinical outcomes. The demonstration of regional neurochemical and global microanatomic brain differences by sex may also raise questions about utility of these factors for defining sex of individuals.

Sex hormones, brain development and hormonal environmental contaminants

Roles of maternal- and fetal-derived sex steroid hormones in brain feminization or masculinization have long been recognized.^53–55 During gestation of mammals, a timed testosterone surge initiates masculinization of the developing brain, while absence of such a surge begins the pathway to a female brain that continues into the prepubertal period.^55,56 These hormones profoundly affect sexual function and differentiation of neural circuits that control female and male behavior. ⁵⁷ The past few generations of humans have seen a dramatic increase in environmental contaminants that possess hormone mimicking properties, which may suggest the possibility of subtle modulation of normal brain sex differentiation in some portion of the human population. These chemicals include the already-discussed ubiquitous DDT that is detectable in most humans, other high-production pesticides and herbicides, and plastics production molecules such as the highly-studied estrogenic and antiandrogenic bisphenols. Bisphenol A (BPA) in particular has been among the most heavily synthesized chemicals over the past 3 decades as use of plastics has increased, with annual production reaching millions of tons. ⁵⁸ Because of growing endocrine disrupting concerns, BPA is more recently being replaced by other bisphenols in plastics production including bisphenol S and bisphenol F, for which there is less available toxicity data.

Human bisphenol exposure has occurred primarily through the diet with levels for BPA estimated at 14–68 ng/kg body weight/day. ⁵⁹ Studies of plastics industry workers who were occupationally exposed to higher levels of BPA found evidence of diverse human endocrine disrupting potential in the forms of increased male sexual dysfunction, reduced semen quality, altered levels of reproductive hormones including prolactin, 17β-estradiol, progesterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH), and altered sex hormone binding globulin (SHBG) in the blood. ⁶⁰ BPA-associated developmental toxicity was also detected in children of the female workers, in the form of shortened male offspring anogenital distance ⁶¹ and decreased offspring birth weight. ⁶² Diethylhexyl phthalate (DEHP) is another high-production plasticizer and cosmetics ingredient to which humans have been widely exposed, and, like BPA, has recently gained recognition for its endocrine disrupting activity. ⁶³

The number of environmental contaminants like DDT and BPA that have achieved ubiquitous ranking has again been growing over the past few generations, meaning increasing numbers of global contaminates. Human-introduced chemicals now considered as ubiquitous include (this list is not exhaustive) numerous pesticides and herbicides used in agriculture,^64–66 different classes of flame retardants including per- and polyfluoroalkyl agents (PFAS), ⁶⁷ pharmaceutical personal care products (PPCP) including birth control pills that generate large quantities of urine-carried hormones and hormonal metabolites in waste waters, ⁶⁸ solvents such as trichloroethylene used industrially for degreasing machine parts and for dry cleaning of clothing, ⁶⁹ plastics and microplastics, ⁷⁰ toxic metals that have recently come to include lithium from increased use of lithium batteries, ⁷¹ and vast quantities of the already-mentioned plasticizers. Of growing concern, many of these chemical contaminants that have achieved global environmental distribution have been found to possess endocrine modulating activity in animals and humans, and in humans have been linked to disrupted endocrine signaling, altered reproductive rhythms, reduced male fertility, neurologic damage, increased risk of autism, ADHD and learning disorders, reduced IQ and additional effects that are in part believed to derive from changes in brain development.^66,72,73

Non-genetic contributions to transgender identity

Counselors and therapists have identified societal and environmental contributions to sexual identities including transgender identity, which may occur over varying numbers of years after the birth of a person. Among these for some transgender individuals are adverse childhood events including the experiencing of childhood sexual abuse from siblings or adult family or non-family members.^74–77 For studies of a genetic component of same sex orientation (SSO) in humans, identical twin studies have been widely used and have shown high levels of twin non-concordance (meaning, the identical twin of a SSO person in most cases does not identify as SSO themselves). This co-presence of identical DNA with opposite self-identified sexual orientations in the majority of twin pairs has been viewed as compelling evidence that the DNA base pair sequence does not include coding for SSO genes.^78–81 Adding to these twin studies, a very large-scale, genome-wide study of 477,522 individuals recently looked for genetic associations with SSO, and found only five loci that showed a significant association. These authors concluded their overall results did not permit a meaningful genome-based prediction of a person’s sexual orientation. ⁸² Based on studies such as these and a large collective body of earlier research, B. Jordan published her recent article “End of the road for the homosexuality gene.” ⁸³ This lack of identifying a genetic basis for SSO has recently led human sexuality researchers to recommend abandoning the “born that way” platform for SSO.^84–86

As with SSO, identical twin studies have found a high level of non-concordance for transgender identity, with 80% of transgender twins having a non-transgender twin counterpart. ⁸⁷ This outcome provides additional evidence that factors outside the DNA base pair sequence underlie development of some transgender identities, and might be used to argue that “born transgender” is an inaccurate conclusion. Newer data, however, suggest the possibility of a DNA-related developmental basis for some transgender identities, and imply that science-based calls to abandon the potential reality of being born transgender may be premature.

Endocrine disruption and epigenetic modification

Epigenetic changes including DNA methylation and histone modification are part of normal fetal and early postnatal programming and development, including fetal neuro-hormonal regulation for establishing typical patterns of differential brain development between females and males.^88–90 Alterations in normal epigenetic control of fetal brain development have been linked to neurologic, psychiatric, and developmental disorders, suggesting importance of normal occurrence of these modifications.^91–94 Gonadal hormone-driven epigenetic modification differences in brain development have also been shown to have regulatory roles in sexual differentiation of the brain.^95,96 A growing number of environmental chemicals, including the already described DDT, BPA and DEHP, have become recognized for ability to cause epigenetic modifications that include histone modification, DNA methylation, and expression of non-coding RNAs.^97–99 These collective observations raise questions about the possibility that environmental pollutants in some cases may be affecting human brain sex development through inappropriate brain epigenetic modifications, particularly when exposure occurs during highly sensitive stages of development. A growing body of research animal data may support this possibility.

Exposure of pregnant laboratory mice to BPA at only 20% of levels presently viewed as safe and allowed for humans, caused changes in the offspring lasting into adulthood that included decreased or eliminated normal sex-difference behaviors. ¹⁰⁰ A later study that also used low-dose BPA exposure in pregnant mice again reported long-term disruption of sexually-dimorphic behaviors, with the female mice showing adulthood behavioral profiles normally displayed by males. ¹⁰¹ Observations that such developmental effects can be transgenerational (i.e., the 2^nd or later generations may continue to show the effect, without themselves having been exposed to the chemicals) have been seen as support for an epigenetic mechanism for the heritability of the observed effects.^102–105

In pregnant laboratory rats, single or combined exposure to BPA and DEHP, again at levels of each plastics chemical approved as safe for humans (5 μg/kg and 7.5 μg/kg, respectively), caused neurobehavioral changes in the offspring at adulthood. The prenatal-exposed female rats showed significant increases in brain norepinephrine in the prefrontal cortex and hippocampus as adults, and enhanced anxiolytic effects and maladaptive defensive behaviors, while the males showed marked reduction of dopamine in the paraventricular hypothalamic nucleus and enhanced feminization.^63,106 These differences in the prefrontal cortex, hippocampus, and paraventricular nucleus all represent neurochemical changes in key brain regions that control sexual and reproductive behaviors.^107–109 Such altered sex-difference behaviors and brain neurochemical profiles in adult mice or rats after low-level prenatal chemical exposure is evidence these animals experienced changed programming during fetal or very early postnatal life.

Because adult human females may be exposed to exogenous estrogen through hormone replacement therapy or by use of oral contraceptives, some of the above-described female rats exposed before birth to BPA and/or DEHP were also exposed, after reaching adulthood, to estrogen (17β-estradiol) and evaluated for brain neurotransmitter and behavioral changes. Among the estrogen-dosed adult rats, those that had been exposed prenatally to low levels of the plastics chemicals showed increased anxiety and reduced active coping abilities in an elevated maze test, increased circulating corticosteroid levels, increased norepinephrine and serotonin in the paraventricular nucleus of the brain, and increased norepinephrine and dopamine in the hippocampus. ¹¹⁰ Brain neurochemical results of this sort were viewed as noteworthy by the authors, given the rats were exposed to chemicals to which the past 2-3 generations of humans have been exposed at increasing rates, including pregnant women, and at levels that have been viewed as allowable for humans. Understanding the diverse influences of inappropriate early-life epigenetic programming by environmental chemical exposures is, consequentially, being viewed as an important consideration for health protection in humans.^{63,106,110,111}

Even though they do not involve changes in the DNA base pair sequence (the code itself), chemical-induced epigenetic modifications may nonetheless represent heritable changes that can be passed from parents to offspring, possibly including later-generation children who have not experienced the chemical exposure. A heritable component of human breast cancer may involve, for instance, an epigenetic modification mediated by early-life exposure to endocrine disrupting chemicals. ¹¹² Also, male-mediated developmental toxicity (harmful chemical exposure effects passed to the children through the father’s sperm), while once considered to be of limited importance, is now recognized as occurring due to epigenetic modifications of the DNA carried by the sperm.^113,114 However, the possible full spectrum of how altered early-life epigenetic programming by endocrine-disrupting environmental chemicals may have affected the human population over the past few generations, remains almost totally unknown.

Epigenetics and brain feminization or masculinization

Pre-birth epigenetic modifications of DNA have been related to fetal androgen signaling patterns regulating brain sex development. ¹¹⁵ Specifically, these authors showed decreased androgen sensitivity in human XX fetuses and increased androgen sensitivity in XY fetuses as a consequence of epigenetic modifications. Such fetal androgen signaling strongly influences brain sex development, which led the authors to hypothesize that inappropriate epigenetic modifications can masculinize the brains of human females during fetal development, and feminize the brains of developing males.^116,117

Brain development can be changed through additional pathways that may be subject to modulation by environmental chemicals. The microglia are an immune cell type located throughout the brain and spinal cord, that regionally account for 5-15% of brain cells. ¹¹⁸ During development, these cells play critical roles in synaptic organization, or “wiring” of the brain. This brain organization is different by sex (female vs. male) in steroid-sensitive regions that are responsible for sociosexual and mood-related behaviors, suggesting potential for vulnerability to endocrine disruption. Epigenetic mechanisms have been found to play key roles in normal brain-regional microglial clearance activity, disruption of which can again lead to neurodegenerative and psychiatric disorders. ¹¹⁹ When a promiscuous rat species and a monogamous prairie vole species were exposed to BPA prior to birth, changes in social and emotional behaviors and in sex-specific colonization of the brain hippocampus and amygdala regions by microglia were detected in both species, however potential epigenetic contributions were not evaluated. ²⁶ These authors noted that developmental exposure to BPA has been associated with altered sociosexual behavior in research animals and in children, and concluded that early-life exposure to endocrine disrupting chemicals may perturb species- and sex-specific colonization of the brain by microglia.

The observation that human males on average perform better than females in tests of spatial visualization has already been described. In what may be related, low-dose exposure of pregnant rats to BPA resulted in improved performance on spatial learning tests in the adult female offspring, in a manner that indicated chemical-induced masculinization of their brains. ²⁴ Regarding dose levels of BPA that were able to cause this brain masculinizing effect in the female offspring, these authors concluded the European Food Safety Authority (EFSA) tolerable human intake level for BPA, of 4 μg/kg body weight per day, is likely to be insufficiently low to be protective against its possible endocrine disrupting effects in developing humans. Specifically, the authors suggested that levels of BPA viewed as safe by the EFSA, may not be broadly safe for normal human brain sex development.

These and a rapidly growing list of additional scientific studies suggest that chemicals like BPA and DDT, ubiquitous contaminants readily detected in urine and blood of most humans,^120,121 may have the potential to influence brain sex development in humans. It then must be considered that BPA and DDT are only two of large numbers of endocrine-active chemicals that humans have synthesized and widely distributed into the environment, resulting in regionally-varying complex mixtures exposures in the human population. With this, it might be considered that different classes of neurologic-based disorders have been increasing the past few generations in the United States and other countries, including but not limited to anxiety, depression, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder, and autism, and have also been related to endocrine disruption caused by environmental chemicals.^{24,101,122,123}

Summary

Many chemicals used to control pests, for instance insecticides for crop protection, were designed to be selectively “more toxic” in insects than humans. The enhanced sensitivity of insects has often been in the form of considerably greater neurotoxicity than is seen in humans, meaning the insects can be killed by doses of chemical that are well below those causing overt neurotoxicity in humans. An oversight that occurred with many pesticides was the later realization that, in addition to the desired selective neurotoxicity, the chemicals also possessed less selective endocrine disrupting activities. These exposures are then added to by other endocrine disrupting agents such as BPA and DEHP in plastics or other products of very common human exposure. Contamination of the environment with such chemicals has been associated with hormone-related changes in diverse wildlife species, particularly when the exposures occurred during sensitive stages of development. A natural concern is that some of the humans, both cis- and transgender, who coinhabit a globally-contaminated planet may also be subtly affected, including in the development of steroid-sensitive brain regions that regulate brain sex establishment.

Clearly, transgender humans long predate modern endocrine disrupting environmental chemicals and have throughout history been a portion of the human population. ¹²⁴ In a world that has gained ubiquitous contamination with endocrine disrupting chemicals, an environmental component to some human phenotypic males (humans born with male genitalia and other typical male physical traits) who are also genotypically male (possess XY chromosomes), but whose brains strongly assure them they are female (transgender)^125,126 may be supported by the chemical and animal data reviewed in this report. The same is of course true for some transgender individuals who phenotypically and genotypically present as female, but whose brains tell them they are male. Regarding transgender, the available literature supports the possibility that non-genetic but DNA-carried, environmentally-induced epigenetic modifications, in some individuals, may influence adulthood gender identities. Based on this growing database, the possibility should not be dismissed that some humans can be born with brain microanatomic and neurochemical architecture that underlies identifying as the sex trans to their body phenotype and genotype. The recognizing of scientific support for this possibility may be of value to humans who very strongly perceive their gender identity to be a hard-wired reality present since time of birth (i.e., “born that way”), rather than a choice made by them. ¹²⁷ The position of gender binary (only 2 genders, female or male) is then strongly supported by human macroscopic anatomic phenotypes and the typical XX or XY genomes (these being the factors most commonly used to deny the reality of transgender people). However, data surveyed in this review also lend support to the possibility of some level of a nonbinary brain gender continuum in the human population due to ubiquitous endocrine modulating environmental chemicals. A relevant question then becomes, when designating individuals as female or male, which basis may be more appropriate; body phenotype and genotype, or brain microanatomy and neurochemistry?