Environmental pollution can disturb steroidgenesis
"During the past 70 years, there was an average production of 1000–2000 new chemical compounds per year, most of them being harmful or environmentally toxic. After disasters such as those in Seveso, Italy, in 1976 or Bhopal, India, in 1984, where thousands of people were harmed and 200,000 had to be epidemiologically monitored and after estimations that about 40% of annual deaths are related to chemical pollution, the health risk of these chemicals became evident and stricter laws came into effect. These different environmental pollutants such as plasticizers, pesticides, or heavy metals can cause direct damage to cells in the germinal epithelium such as the Sertoli cells leading to low sperm counts. The effect can also be on the Leydig cells where steroidogenesis is disturbed. Similar effects will take place if the hypothalamus–pituitary–gonadal axis is affected by endocrine disruption. As a result, changes in the sex ratio, congenital malformation such as hypospadias, or cancers can develop. Therefore, there is an urgent need to reduce environmental pollution to ensure future generation's well-being."
(Giwercman, Aleksander, and Yvonne Lundberg Giwercman. "Environmental factors and testicular function." Best practice & research Clinical endocrinology & metabolism 25.2 (2011): 391-402.)
See also the Wikipedia article on Xenoestrogens.
See also the Wikipedia article on Xenoestrogens.
"Nonylphenol (NP) and di-n-butyl phthalate (DBP), two well-known EDCs, are high-production volume chemicals widely distributed in the environment. NP and phthalates can leach from products that contain them and accumulate in the environment [2]. Such environmental toxicants can be taken up by humans through ingesting contaminated food or water. Recent studies suggest that environmental levels of NP may exert estrogenic effects in humans and wild animals, disturbing the balance of hormone secretion and cytokine network at the maternal-fetal interface [3], [4]. Exposure to DBP, also referred to as antiandrogen, between gestation days (GD) 12 and 21 disrupts sexual development in rats, leading to decreased anogenital distance, reproductive tract malformations, seminiferous tubule degeneration, interstitial cell hyperplasia and adenoma in the testis, as well as small reproductive organs in male F1 rats [5]. Monobutyl phthalate (MBP) [5], [6], the active monoester metabolite of DBP, can inhibit the fetal testosterone synthesis resulting in anti-androgenic effects [7]–[9]."
(Hu, Yang, et al. "Antagonistic effects of a mixture of low-dose nonylphenol and di-n-butyl phthalate (monobutyl phthalate) on the Sertoli cells and serum reproductive hormones in prepubertal male rats in vitro and in vivo." PloS one 9.3 (2014): e93425.)
Glyphosate at "safe" dosage linked to masculinization of both male and female rats
"The present pilot study examine whether exposure to GBHs at the dose of glyphosate considered to be “safe” (the US Acceptable Daily Intake - ADI - of 1.75 mg/kg bw/day), starting from in utero life, affect the development and endocrine system across different life stages in Sprague Dawley (SD) rats. (...)
The present pilot study demonstrate that GBHs (Glyphosate-based herbicides) exposure, from prenatal period to adulthood, induced endocrine effects and altered reproductive developmental parameters in male and female SD (Sprague Dawley ) rats. In particular, it was associated with androgen-like effects, including a statistically significant increase of AGDs (anogenital distance) in both males and females, delay of FE (Age at first estrous) and increased testosterone in female."
(Manservisi, Fabiana, Corina Lesseur, Simona Panzacchi, Daniele Mandrioli, Laura Falcioni, Luciano Bua, Marco Manservigi et al. "The Ramazzini Institute 13-week pilot study glyphosate-based herbicides administered at human-equivalent dose to Sprague Dawley rats: effects on development and endocrine system." Environmental Health 18, no. 1 (2019): 15.)
Pregnant women's exposure to Triclosan increases offspring's testosterone levels (especially in males)
"Triclosan (TCS) has been widely detected in pregnant women. [...] Prenatal TCS exposure was associated with increased testosterone concentrations in cord blood in a dose-dependent manner. [...] Of note, prenatal TCS exposure was associated with increased testosterone and decreased E2 (estradiol) concentrations in cord blood among male infants."
(Wang, Caifeng, et al. "Impacts of prenatal triclosan exposure on fetal reproductive hormones and its potential mechanism." Environment International (2017).)
"Triclosan [...] is an antibacterial and antifungal agent found in some consumer products, including toothpaste, soaps, detergents, toys, and surgical cleaning treatments. [...] Humans are exposed to triclosan through skin absorption when washing hands or in the shower, brushing teeth, using mouthwash or doing dishes, and through ingestion when swallowed. When triclosan is released into the environment, additional exposure to the chemical is possible through ingesting plants grown in soil treated with sewage sludge, or eating fish exposed to it."
(Wikipedia, Triclosan)
Prenatal alcohol reduces testosterone and increases left-hand digit ratios in rats
"Since prenatal alcohol can reduce testosterone in rats, the effects of prenatal alcohol were measured on rat digit length. [...] Rats exposed to [a high dose] 6 g/kg of ethanol had smaller digits than controls on both forepaws and higher digit ratios than controls on the left forepaw. Rat digit ratios differ between the sexes, and prenatal alcohol exposure affects digit ratios. The results are consistent with a perinatal disruption of testosterone levels by alcohol and/or of testosterone's effects on digit length and ratios."(McMechan, Andrew P., et al. "Effects of prenatal alcohol exposure on forepaw digit length and digit ratios in rats." Developmental psychobiology 45.4 (2004): 251-258.)
Gene pools affect 2D:4D ratio, geopgraphical latitude does not
"Studies have reported a difference in this ratio between Caucasian males in Britain and in the U.S.: higher average 2D:4D ratios were obtained in Britain. This raises the question of whether differences among different Caucasian gene pools were responsible or whether some environmental variable associated with latitude might be involved (e.g., exposure to sunlight or different day-length patterns). This question was explored by examining 2D:4D ratios for an Australian adolescent sample. The Australians were predominantly of British ancestry, but lived at distances from the equator more like those of the U.S. studies. The Australian 2D:4D ratios resembled those in Britain rather than those in the U.S., tending to exclude hypotheses related to latitude and making differences in gene pools a plausible explanation."(source: Population Differences in Finger-Length Ratios: Ethnicity or Latitude?, John C. Loehlin, Ph.D., Dennis McFadden, Ph.D., Sarah E. Medland, Ph.D., and Nicholas G. Martin, Ph.D., Archives of Sexual Behavior, Vol. 35, No. 6, December 2006, pp. 739–742, retrieved July 1st 2016)
"We concluded that the sex differences in Chinese 2D:4D are consistent with the results from western studies, and that genetic pool differences rather than latitude-related environmental variables affect the 2D:4D in China. In addition, 2D:4D measurements obtained by different digit measurement techniques should not be combined within one study, or used together in comparative studies."
(source: The digit ratio (2D:4D) in China: A meta-analysis, Yin Xu, Yong Zheng, American Journal of Human Biology, 2014, DOI: 10.1002/ajhb.22639)
Prenatal alcohol exposure related to elevated testosterone in adolescents
"Prenatal alcohol exposure was related to elevated testosterone concentrations for males and females but not to changes in Tanner stages or age at menarche ( = first menstrual cycle). [...] This study was the first to show a relation between prenatal alcohol exposure and increased testosterone during adolescence and evidence of decreased testosterone responsiveness in tissues related to pubertal development."
(Carter, R. Colin, et al. "Effects of prenatal alcohol exposure on testosterone and pubertal development." Alcoholism: Clinical and Experimental Research 38.6 (2014): 1671-1679.)
(And ASD has been linked with lower 2D:4D ratios and high prenatal testosterone, see the items on autism, ASD and Asperger's in Effects of (fetal) testosterone on brain and behavior).
(The Tanner scale (also known as the Tanner stages) is a scale of physical development in children, adolescents and adults. The scale defines physical measurements of development based on external primary and secondary sex characteristics, such as the size of the breasts, genitals, testicular volume and development of pubic hair.)
(Wikipedia, Tanner scale)
Inbreeding associated with lower, more masculine-type 2D:4D ratios in offspring
"Across hands and sex, consanguineous parentage was consistently associated with lower, more masculine-typical, digit ratios."(Özener, Baris, Peter L. Hurd, and İzzet Duyar. "Inbreeding is associated with lower 2D: 4D digit ratio." American Journal of Human Biology 26.2 (2014): 183-188.)
"Our study from large population in India concludes that consanguinity increases the risk for ASD with an odds ratio of 3.22."
(Mamidala, Madhu P., et al. "Consanguinity in India and Its Association With Autism Spectrum Disorder." Autism Research 8.2 (2015): 224-228.)
(And ASD has been linked with lower 2D:4D ratios and high prenatal testosterone, see the items on autism, ASD and Asperger's in Effects of (fetal) testosterone on brain and behavior).
In sheep, mother's nicotine exposure increases prenatal testosterone of fetuses
"We conclude that prenatal nicotine exposure increases plasma testosterone levels chronically in adolescent female rat offspring and acutely in both male and female ovine fetuses."
(Smith, Lynne M., et al. "Prenatal nicotine increases testosterone levels in the fetus and female offspring." Nicotine & tobacco research 5.3 (2003): 369-374.)
Correlation between physical and sexual maternal activity during pregnancy, and masculine traits in female offspring
"By and large, as maternal physical activity increased, feminine mannerisms decreased and masculine mannerisms increased in the offspring, particularly for females. Maternal physical activity was also associated with increased upper- and lower-body strength and especially with adult height among offspring. Sexual activity by the mother was only associated with upper-body strength and adult height, particularly of the female offspring. Several sexually dimorphic physical traits in offspring are associated with maternal activity levels during pregnancy. Prenatal testosterone is almost certainly involved. The associations could either reflect genetic influences (given that prenatal testosterone is highly heritable) or an effect of maternal testosterone being transferred to the developing fetus. More research is needed to assess the relative merit of these two possibilities."(J Biosoc Sci. 2017 Apr 3:1-10. doi: 10.1017/S0021932017000074. [Epub ahead of print], MATERNAL ACTIVITY DURING PREGNANCY AND SEXUALLY DIMORPHIC TRAITS IN OFFSPRING. Ellis L, Eisenman R, Hoskin A)
Exposure of rat fetuses to phenobarbital lowers testosterone in plasma and brain for rest of life
"Exposure of rats to phenobarbital during late prenatal development decreased the concentration of testosterone in plasma and the brain during the late fetal, early postnatal, pubertal, and adult periods, By decreasing the production of testosterone in the brain during the period of sexual differentiation, phenobarbital may lead to sexual dysfunction in later life."(Gupta, Chhanda, Sumner J. Yaffe, and Bernard H. Shapiro. "Prenatal exposure to phenobarbital permanently decreases testosterone and causes reproductive dysfunction." Science 216.4546 (1982): 640-642.)
2D:4D digit ratio is highly heritable
"PT (Prenatal Testosterone) levels are highly heritable".(Blanchard, Alyson, and Luna C. Munoz Centifanti. "Callous-Unemotional Traits Moderate the Relation Between Prenatal Testosterone (2D: 4D) and Externalising Behaviours in Children." Child Psychiatry & Human Development (2016): 1-10., citing the study below)
(Gobrogge, Kyle L., S. Marc Breedlove, and Kelly L. Klump. "Genetic and environmental influences on 2D: 4D finger length ratios: A study of monozygotic and dizygotic male and female twins." Archives of Sexual Behavior 37.1 (2008): 112-118.)
"Overall, biometric model-fitting analyses indicated significant additive genetic and nonshared environmental influences on digit ratios. Findings suggest greater similarity between 2D:4D ratios in MZ (monozygotic) relative to DZ (dizygotic) twins that can be accounted for by genetic and nonshared environmental factors."
"Heritability was estimated to be approximately 66% for 2d:4d (...). [...] These results suggest a substantial genetic contribution to the determination of this hormonally related skeletal ratio in women, which could be more influential than the effects of common prenatal environmental factors." (study on female twins)(Paul, Simon N., et al. "Heritability of the second to fourth digit ratio (2d: 4d): A twin study." Twin Research and Human Genetics 9.02 (2006): 215-219.)
"[P]arent‐offspring (0.15‐0.28, P < .001) and sibling correlations (0.13‐0.38, P < .009) were found to be significant. (...) thus indicating the existence of a clear familial aggregation of 2D:4D ratio variation in the Chuvashian pedigrees, which cannot be explained only by common environmental effects."(Kalichman, Leonid, Valery Batsevich, and Eugene Kobyliansky. "Heritability estimation of 2D: 4D finger ratio in a Chuvashian population‐based sample." American Journal of Human Biology: e23212.)
Mother's exposure during pregnancy to stress and estrogens in food and chemicals may be linked to autism in children
"Mothers of children with ASD reported higher consumption of non-hormone free animal products, reported putting more endocrine mimicking chemicals on their bodies daily than control mothers, and reported having “very high” levels of stress during their pregnancies compared to control mothers. Furthermore, mothers of children with ASD reported a higher incidence of traumatic events during their pregnancies, specifically during the pregnancy with their child that received an ASD diagnosis, and a higher lifetime incidence of PTSD. Overall, there are significant differences related to maternal estrogen exposure between the pregnancies of mothers with and without a child with ASD. These results suggest that future research should investigate the possibility of a direct link between maternal(Bunker, Sarah. "Maternal estrogen exposure may be linked to an increased risk of autism spectrum disorder." (2017).)
estrogen exposure and autism risk."
Maternal age and 2D:4D strong determinant of children's 2D:4D, periconceptual smoking not
"Age and maternal 2D:4D were strong determinants of the children’s 2D:4D, however, the mean 2D:4D did not differ among children whose mothers had smoked during the periconceptional period (i.e. 1 year before through the first trimester of pregnancy) compared with those who had not, irrespective of sex. In conclusion, we did not find an association between maternal periconceptional smoking and children’s 2D:4D, although the smoking prevalence was low."(Velez, M. P., et al. "Is maternal periconceptional smoking associated with 2D: 4D digit ratio in their children?.")
2D:4D not influenced by prenatal exposure to famine
"The 2D:4D ratio is not significantly affected by prenatal exposure to famine."
(Stein, Aryeh D., Henry S. Kahn, and L. H. Lumey. "The 2D: 4D digit ratio is not a useful marker for prenatal famine exposure: Evidence from the Dutch hunger winter families study." American Journal of Human Biology 22.6 (2010): 801-806.)
Low digit ratios in early hominids and humans, except Australopithecus
"Pierolapithecus catalaunicus, Hispanopithecus laietanus and Ardipithecus ramidus have ratios consistent with polygynous extant species (low 2D:4D), whereas the ratio of Australopithecus afarensis is consistent with monogamous extant species (high 2D:4D). The early anatomically modern human Qafzeh 9 and Neanderthals have lower digit ratios than most contemporary human populations, indicating increased androgenization and possibly higher incidence of polygyny."(Nelson, Emma, et al. "Digit ratios predict polygyny in early apes, Ardipithecus, Neanderthals and early modern humans but not in Australopithecus." Proceedings of the Royal Society of London B: Biological Sciences 278.1711 (2011): 1556-1563.)
"Australopithecus [...] were the first hominids to possess genes, known as the duplicated SRGAP2, which increased the length and ability of neurons in the brain.[2] One of the australopith species eventually became the Homo genus in Africa around two million years ago (e.g. Homo habilis), and eventually modern humans, H. sapiens sapiens."
(Wikipedia, Australopithecus, accessed 2017/26/05)
(Balthazart, Jacques. "Sexual orientation in all its aspects.", Reflexions, le site de vulgarisation de l'Université de Liège, Université de Liège - http://reflexions.ulg.ac.be/ - 06 July 2017)
More maternal exposure to light toward end of 1st prenatal trimester predicts low 2D:4D in offspring
"Low 2D:4D (high prenatal testosterone) is found in Winter Births.
The effect is greatest for births in the first part of the 20th Century.
Day length towards the end of the 1st Trimester predicts 2D:4D
Our results support the solstititial-melatonin-testosterone hypothesis"
"Participants born in the late-Autumn and who experienced long days in the 2nd and 3rd prenatal months had low 2D:4D. The effects were strongest for early 20th Century births where photoperiods would be less disrupted by artificial light."(Szwed, Anita, Magdalena Kosinska, and John T. Manning. "Digit ratio (2D: 4D) and month of birth: A link to the solstitial-melatonin-testosterone effect." Early Human Development 104 (2017): 23-26.)
2D:4D transmitted from mother to daughter but not mother/father to son
"Correlations between 2D:4D of parents and children, as well as between mothers and fathers were conducted. 2D:4D was also examined in relation to age and sex.(Richards, Gareth, Wynford Bellin, and William Davies. "Familial digit ratio (2D: 4D) associations in a general population sample from Wales." Early Human Development 112 (2017): 14-19.)
Results and conclusions:
(...) Within the dyads, there was a significant positive correlation between mother and daughter 2D:4D, but no significant correlation between mother and son ratios, nor between father and offspring ratios. The overall pattern of correlations (with emphasis on father-son dyads) was not supportive of Y-linkage. There was a positive correlation between 2D:4D and age in children, and a negative correlation between 2D:4D and age in adults, and no evidence of assortative mating. Our data are consistent with the notion of 2D:4D as a sexually-dimorphic, mildly age-sensitive, and transgenerationally-transmitted trait that is more likely to be X- than Y-linked."
Prenatal androgen exposure may be related to maternal age and weight gain during pregnancy
"Multiparity ( = -0.28, p < 0.001), self-rated depression ( = 0.26, p < 0.001), and weight gain ( = 0.18, p < 0.05) were independent explanatory factors for the maternal total testosterone levels. Maternal age ( = -0.34, p < 0.001), weight gain ( = 0.19, p < 0.05), and amniotic fluid cortisol levels ( = 0.44, p < 0.001) were independent explanatory factors of amniotic fluid testosterone in female fetuses, explaining 64.3 % of the variability in amniotic fluid testosterone.(Kunovac-Kallak, Theodora, et al. "Maternal and female fetal testosterone levels are associated with maternal age and gestational weight gain." European Journal of Endocrinology (2017): EJE-17.)
Wider implications of the findings: Young maternal age and excessive maternal weight gain may increase the prenatal androgen exposure of female fetuses. Further studies are needed to explore this finding."
Testosterone transmits poorly from maternal into fetal body (study on rats)
"In the present study it was found that doses of 10 and 25 mg testosterone propionate (TP) given to pregnant rats could induce the early-androgen syndrome. These doses caused delayed parturition with intra-uterine death and inhibition of lactation with early post-natal death of the young; these events could be avoided by Caesarian section and foster mothers.(Swanson, H. E., and JJ van der Werff ten Bosch. "THE» EARLY-ANDROGEN «SYNDROME; EFFECTS OF PRE-NATAL TESTOSTERONE PROPIONATE." Acta endocrinologica 50.3 (1965): 379-390.)
In other experiments TP was injected directly into the foetuses or their amniotic sacs. A dose of 20 μg into the amniotic sac was without effect on subsequent ovarian activity and, with one exception, on the external genitalia of the young. Injection of 20 or 100 μg into the foetus caused both external masculinization and anovulatory ovaries.
The apparent low sensitivity of the foetus to TP injected into the pregnant doe seems to be due to poor transmission of the steroid from the maternal into the foetal body. The foetal external genitalia appear to be more sensitive to TP than the mechanism which sets the future gonadotrophic pattern of the brain-pituitary complex."
11 pesticides, fungicides and pharmaceuticals identified that suppress testosterone synthesis in fetal testes cell cultures; effect increased when mixed together
"Numerous chemicals have been identified as antiandrogens in experimental animals and cell-based systems and have been shown to induce androgen insufficiency by several modes of action: suppressing androgen synthesis, blocking the androgen receptor, or altering the signaling of local mediators such as prostaglandins. Prominent examples of anti-androgenic chemicals include certain phthalates used as plasticizers, pesticides, and mild analgesics (...).(Gaudriault, Pierre, et al. "Endocrine Disruption in Human Fetal Testis Explants by Individual and Combined Exposures to Selected Pharmaceuticals, Pesticides, and Environmental Pollutants." Environmental Health Perspectives 87004: 1.)
[...]
Candidate chemicals were selected for inclusion in our multi-component mixtures if they met the following criteria: a) They had to be able to suppress testosterone synthesis in the FEGA, and b) they had to show dose–response curves with almost complete inhibition of testosterone synthesis. (...) Furthermore, all selected chemicals had to be of relevance to human exposures. (...) 11 compounds qualified for inclusion in our mixtures [namely Ketoconazole, BPA, Valproic acid, Clomiphene, Theophylline, BPS, Chlordecone, Imazalil, Bitertanol, Prochloraz, and Propiconazole]. (...) [Our work] uncovered several new chemicals whose capability of suppressing testosterone synthesis in humans was not previously recognized: the pesticide imazalil, (...); the pesticides propiconazole and bitertanol, (...) and the fungicide prochloraz and the selective estrogen receptor modulator clomifen (...), [t]heophylline, a caffeine metabolite and pharmaceutical used in the treatment of asthma (...) [,] the teratogenic drug valproic acid and the pesticide chlordecone.(...)
OBJECTIVES:
Our aim was to investigate whether chemicals can act together to disrupt androgen production in human fetal testis explants and to evaluate the importance of mixture effects when characterizing the hazard of individual chemicals.
RESULTS:
We evaluated mixtures composed of four and eight antiandrogens that contained the pharmaceuticals ketoconazole and theophylline and several previously untested chemicals, such as the pesticides imazalil and propiconazole. Mixtures of antiandrogens can suppress testosterone synthesis in human fetal testicular explants to an extent greater than that seen with individual chemicals. This revealed itself as a shift towards lower doses in the dose–response curves of individual antiandrogens that became more pronounced as the number of components increased from four to eight."
Meat-eating correlated with low 2D:4D ratio
"The key factor impacting offspring development (including prenatal androgen levels) appears to be diet, both in terms of shortage and excessive intake of certain food products. (...) One of the findings is that countries with high meat consumption present the so-called masculine digit ratio, while countries with plant-based diets - a feminine digit ratio."(Modlinska, Klaudia, and Wojciech Pisula. "exploratory analysis of the Links among Food Consumption profiles, prenatal androgens, and selected Measures of Quality of Life." Frontiers in public health 4 (2016).)
Hyperplasia of adrenal glands causes embryonic exposure to abnormally high levels of androgens
"There are illnesses which affect the embryonic hormonal balance [...]. For example, hyperplasia of the adrenal glands consists of an abnormal development of these glands which then no longer secrete cortisol but which produce androgens instead. "The girls affected are often exposed to much higher levels of male hormones than normal during the course of their embryonic life. This results in a masculinisation of genital structures. Some are born with a fusion of the lips or a clitoris the size of a penis etc.", explains Jacques Balthazart."(Balthazart, Jacques. "Sexual orientation in all its aspects.", Reflexions, le site de vulgarisation de l'Université de Liège, Université de Liège - http://reflexions.ulg.ac.be/ - 06 July 2017)
Sexual differentiation of mammal brain caused by hormonal, genetic and epigenetic factors
(Balthazart, Jacques. "Sexual orientation in all its aspects.", Reflexions, le site de vulgarisation de l'Université de Liège, Université de Liège - http://reflexions.ulg.ac.be/ - 06 July 2017)
Paracetamol during pregnancy mildly lowers fetal testosterone
"Gestational exposure to acetaminophen causes a mild reduction in fetal testosterone production in the rat and human fetal testis"(Al-Shaikh, Turki M. "Histological Study on the Effects of Captopril, Paracetamol and Their Combination on Testis in Rats.")
Actual testosterone levels are correlated with ambient temperature and season (study on monkeys)
"Fecal T levels correlated with both rank and atmospheric temperature."(Takeshita, Rafaela SC, et al. "Effect of castration on social behavior and hormones in male Japanese macaques (Macaca fuscata)." Physiology & Behavior (2017).)
Environmental factors are primary cause of testicular dysgenesis syndrome
"This review aimed to provide evidence verifying the reality of TDS (testicular dysgenesis syndrome) based on four key aspects: environmental endocrine-disrupting chemicals (EDCs), genetic factors, intrauterine growth disorders and lifestyle factors. (...) In conclusion, our study revealed that environmental exposures owing to modern lifestyles are primary factors involved in the associated trends of the syndrome, which are capable of affecting the adult endocrine system via direct means or through epigenetic mechanisms."
(Xing, Jian-Sheng, and Zhi-Ming Bai. "Is testicular dysgenesis syndrome a genetic, endocrine, or environmental disease, or an unexplained reproductive disorder?." Life Sciences (2017).)
People with Klinefelter syndrome have higher 2D:4D ratio
"Adult KS (Klinefelter syndrome) individuals were taller than their fathers and had shorter fingers than fathers and male controls. Compared with fathers, male controls and mothers, KS males had shorter fingers relative to height. With regard to 2D:4D, KS individuals had higher 2D:4D than fathers (right and left hands), male controls (right and left hands) and mothers (left hands). Among KS males older than 13 years there were 34 individuals currently prescribed testosterone and nine not prescribed. In comparison to the former, the latter individuals had higher right 2D:4D and higher right-left 2D:4D."(Manning, John T., Liam P. Kilduff, and Robert Trivers. "Digit ratio (2D: 4D) in Klinefelter's syndrome." Andrology 1.1 (2013): 94-99.)
Phtalates (plasticizers) reduce testosterone to female levels in male rat offspring
"Phthalate esters (PE) such as DEHP are high production volume plasticizers used in vinyl floors, food wraps, cosmetics, medical products, and toys. In spite of their widespread and long-term use, most PE have not been adequately tested for transgenerational reproductive toxicity. (...) Maternal DEHP treatment at 750 mg/kg/day from gestational day (GD) 14 to postnatal day (PND) 3 caused a reduction in T production, and reduced testicular and whole-body T levels in fetal and neonatal male rats from GD 17 to PND 2. As a consequence, anogenital distance (AGD) on PND 2 was reduced by 36% in exposed male, but not female, offspring. By GD 20, DEHP treatment also reduced testis weight.(...) These data indicate that DEHP disrupts male rat sexual differentiation by reducing T to female levels in the fetal male rat during a critical stage of reproductive tract differentiation."(Parks, Louise G., et al. "The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat." Toxicological sciences 58.2 (2000): 339-349.)
Lavender and tea-tree oil have estrogenic and anti-androgenic properties
"Researchers at the NIEHS, including Kenneth Korach, Ph.D., a co-investigator for the new study, previously found laboratory evidence that lavender and tea tree oil have estrogenic (estrogen-like) properties and anti-androgenic (testosterone inhibiting-like) activities, meaning they compete or hinder the hormones that control male characteristics, which could affect puberty and growth."(The Endocrine Society. "Chemicals in lavender and tea tree oil appear to be hormone disruptors." ScienceDaily. ScienceDaily, 18 March 2018. )
Side-product of Brazilian bio-fuel production is very potent antiandrogenic, and exposure is ubiquitous in Brazil
"Diisopentyl phthalate (DiPeP) exposure in Brazil seems ubiquitous. DiPeP is produced from iso-amyl alcohol, a side product of Brazilian bio-fuel. (...) This unexpected and ubiquitous DiPeP exposure indicates to unique DiPeP exposure sources in Brazil. These exposures spark considerable concern because DiPeP is one of the most potent antiandrogenic phthalates."(Souza, Michele Bertoncello, Marcella Tapias Passoni, Claudia Pälmke, Katlyn Barp Meyer, Amanda Caroline Venturelli, Giulia Araújo, Bruno Sanches de Castilhos et al. "Unexpected, ubiquitous exposure of pregnant Brazilian women to diisopentyl phthalate, one of the most potent antiandrogenic phthalates." Environment International 119 (2018): 447-454.)
Maternal 2D:4D correlates with child's 2D:4D; Time-to-pregancy, infertility and Assisted Reproductive Technologies have no influence on child's 2D:4D
"We aimed to investigate the association between TTP (Time To Pregnancy, the number of menstrual cycles required to conceive), infertility, or use of Assisted Reproductive Technologies (ART) and offspring 2D:4D. (...) The mean 2D:4D (of the offspring) did not differ according to TTP, infertility, or use of ART. The only factors associated with the child's 2D:4D were the child's age and maternal 2D:4D."(Shere, Mahvash, Tye E. Arbuckle, Patricia Monnier, William Fraser, and Maria P. Velez. "Time‐to‐pregnancy and offspring finger‐length ratio (2D: 4D)." American Journal of Human Biology.)
Factors influencing maternal androgen concentrations: with age maternal testosterone concentrations decrease, with BMI they increase, and black women have 18-30% higher androgen concentrations
"Objectives To identify factors predicting maternal sex steroid hormone concentrations in early pregnancy.(Barrett, Emily S., Omar Mbowe, Sally W. Thurston, Samantha Butts, Christina Wang, Ruby Nguyen, Nicole Bush et al. "Predictors of Steroid Hormone Concentrations in Early Pregnancy: Results from a Multi-Center Cohort." Maternal and Child Health Journal (2019): 1-11.)
Methods The Infant Development and the Environment Study recruited healthy pregnant women from academic medical centers in four US cities. Gold standard liquid chromatography–tandem mass spectrometry was used to measure maternal sex steroids concentrations (total testosterone [TT], free testosterone [FT], estrone [E1], estradiol [E2], and estriol [E3] concentrations) in serum samples from 548 women carrying singletons (median = 11.7 weeks gestation). Women completed questionnaires on demographic and lifestyle characteristics.
Results In multivariable linear regression analyses, hormone concentrations varied in relation to maternal age, body mass index (BMI), race, and parity. Older mothers had significantly lower levels of most hormones; for every year increase in maternal age, there was a 1–2% decrease in E1, E2, TT, and FT. By contrast, each unit increase in maternal BMI was associated 1–2% lower estrogen (E1, E2, E3) levels, but 1–2% higher androgen (TT, FT) concentrations. Hormone concentrations were 4–18% lower among parous women, and for each year elapsed since last birth, TT and FT were 1–2% higher (no difference in estrogens). Androgen concentrations were 18–30% higher among Black women compared to women of other races. Fetal sex, maternal stress, and lifestyle factors (including alcohol and tobacco use) were not related to maternal steroid concentrations.
Conclusions for Practice Maternal demographic factors predict sex steroid hormone concentrations during pregnancy, which is important given increasing evidence that the prenatal endocrine environment shapes future risk of chronic disease for both mother and offspring."
People with congenital GH/IGF-1 deficiency have higher 2D:4D digit ratio
"The analyses of our results revealed that patients with congenital GH/IGF-1 deficiency [Growth Hormone/Insuline-like Growth Factor] show an identical 2D:4D ratio for both sexes, but a higher (more feminine) ratio than the normal population. These findings may be explained by a higher estrogen effect resulting from the absence of a functional GH-IGF-1 axis prenatally."(Uchitel, Y., R. Kauli, O. Konen, P. Lilos, and Z. Laron. "The second to fourth digit ratio in patients with congenital IGF-1 Deficiency." Anthropologischer Anzeiger; Bericht uber die biologisch-anthropologische Literatur (2019).)
Higher number of older brothers and number of children in the family increases 2D:4D in boys but decreases 2D:4D in girls
"Birth order, number of siblings (except for younger sisters), and sex ratio in siblings were significantly related to the 2D:4D ratio on the right, left, or both hands. At the same time, the relationships were opposite in males and females for birth order, number of older brothers and number of children in the family––increasing values in these variables increased digit ratio in males but decreased digit ratio in females."(Králík, Miroslav, Adela Hupková, Tomáš Zeman, Martin Hložek, Lukáš Hlaváček, Marie Slováčková, Martin Čuta, and Petra Urbanová. "Family effects on the digit ratio (2D: 4D): The role of the interbirth interval." American Journal of Human Biology (2019): e23260.)
Inbreeding associated with lower digit ratios in offspring
"We determined that inbreeding was related to a reduction in the digit ratios regardless of the side of the hand and the sex of the infant, showing a consistent tendency to appear more masculine. Interaction between marriage type*sex was highly significant.(Ertuğrul, Berna, and Barış Özener. "Relationship between parental consanguinity and digit ratios (2D: 4D) among Turkish newborns in Sivas." American Journal of Human Biology (2019).)
Conclusions
Parental consanguinity appears to cause fetal masculinization of digit ratios by increasing fetal stress among Turkish newborns."
In rats, maternal exposure to ibuprofen has "low testosterone" effects on offspring
"Males [(male offspring of mothers)] exposed to ibuprofen had a decrease in body weight and anogenital distance, as well as a delay in the ages of testicular descent and preputial separation. In adulthood, there was a decrease in the Leydig cells nuclei volume, testosterone levels and percentage of normal sperm morphology. All animals exposed to ibuprofen presented male copulatory behavior, however, in the presence of another male, they also presented a female-typical behavior. Maternal exposure to ibuprofen during the sensitive windows of brain development adversely impacted the reproductive parameters of male rats, suggesting an incomplete masculinization of the hypothalamus."(da Silva Balin, P., Jorge, B. C., Leite, A. R. R., Borges, C. S., Oba, E., Silva, E. J. R., ... & Arena, A. C. (2020). Maternal exposure to ibuprofen can affect the programming of the hypothalamus of the male offspring. Regulatory Toxicology and Pharmacology, 104576.)
Phtalates and BPA exposure increases 2D:4D in boys, not girls; mediated by estrogen receptor ESR1 polymorphism type
"Phthalates and bisphenol A (BPA) are estrogenic endocrine disruptors. Polymorphisms in the gene encoding estrogen receptor 1 (ESR1) may contribute to the ratio of the lengths of the second and fourth digits (2D:4D), which is considered an index of prenatal exposure to sex hormones. Thus, we investigated whether ESR1 polymorphisms modify the effects of prenatal exposure to phthalates and BPA on 2D:4D in a birth cohort. (...)(Nishimura, Y., Moriya, K., Kobayashi, S., Araki, A., Sata, F., Mitsui, T., ... & Nakamura, M. (2020). Association of exposure to prenatal phthalate esters and bisphenol A and polymorphisms in the ESR1 gene with the second to fourth digit ratio in school-aged children: data from the Hokkaido Study. Steroids, 108637.)
Boys with the AG/GG genotype at rs2077647 in the group exposed to high levels of mono(2-ethylhexyl) phthalate (MEHP) or Σ Di(2-ethylhexyl) phthalate (DEHP) showed feminized 2D:4D compared with boys with the AA genotype at rs2077647 who had low exposure to MEHP or ΣDEHP (...). No significant differences were found among girls. There were no associations between mean 2D:4D and metabolites other than MEHP or BPA. These data suggest that ESR1 polymorphisms modify the effects of prenatal exposure to DEHP on mean 2D:4D among boys."
In rats, developmental vitamin D defincieny increases testosterone levels in male foetuses brains
"We show that DVD-deficiency (Developmental Vitamin D) increases testosterone levels in maternal blood. We also show elevated levels of testosterone and androstenedione in the amniotic fluid of female but not male DVD-deficient foetuses. Testosterone levels were also elevated in DVD-deficient male brains."
(Ali, A. A., Cui, X., Pertile, R. A. N., Li, X., Medley, G., Alexander, S. A., ... & Eyles, D. W. (2020). Developmental vitamin D deficiency increases foetal exposure to testosterone. Molecular Autism, 11(1), 1-13.)
Bisphenol analogues associated with higher 2D:4D
"Prenatal exposure to BPA alternatives was associated with offspring’s higher 2D:4D."
(Wang, Z., Zhou, Y., Liang, H., Miao, M., Chen, Y., Zhang, X., ... & Yuan, W. (2021). Prenatal exposure to bisphenol analogues and digit ratio in children at ages 4 and 6 years: A birth cohort study. Environmental Pollution, 278, 116820.)
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