Appendix A: Sex Determination

Sex Determination
*I have found it useful during this research to look up brief summaries of unfamiliar topics or terms in Wikipedia- the reader might
consider a similar practice.

What makes a man a man and a woman a woman? What is the causation of physical sex? What is physical sex? The answers to these questions are neither simple nor straightforward- but parts of those answers are well understood, so we’ll start there. There are two common ways of causing/determining sex in the biological world: 1) nongenetic factors (such as environmental temperature) and 2) genetic factors. Humans fall into the latter category, based on the genotype of chromosome 23: XY individuals are male and XX are female. This genetic difference causes a number of measurably different phenotypes (physical traits)- different shaped faces, different genitalia, different brains, different hands, different hematocrit (red blood cell count), different muscle mass, and different hormone profiles to name just a few. All right, nothing new here so far. How does the genotype difference translate into these phenotypes? Here the answer begins to get more complex. The default phenotype in humans is female. For a short period after an egg is fertilized, the zygote is bipotential, meaning it can become either a male or a female, and has both Mullerian ducts (precursors to the uterus and fallopian tubes) and Wolffian ducts (precursors to the prostate and seminal vesicles). A simplified, two-step explanation of how the default female embryo is converted into a male: Step 1: the SRY (Sex-determining Region Y) gene from the Y chromosome is translated into a protein known as TDF (Testis Determining Factor). Step 2: TDF causes a consequence cascade, which in concert with hormones causes the phenotypic differences observed between males and females. Now, as you might imagine, things can go wrong at a number of points during this process. In Step 1, the SRY gene could be broken or missing- this results in XY, or X_ persons that are phenotypically female (Turner syndrome). The SRY gene could be translocated to an X, resulting in an XX person that’s phenotypically male (XX male syndrome). The SRY gene could be faulty, resulting in an XY phenotypic female (Swyer syndrome). This is just the beginning, though, as these abnormalities result only from Step 1 problems. Step 2 problems are even messier. Step 2 problems also demonstrate why genes are not the whole story when it comes to sex determination. Before I illustrate some Step 2 problems, let me describe epigenetics by comparing the endocrine system to a football team. (note to geneticists- I recognize that epigenetics usually refers to genetic imprinting and

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methylation. Here I follow Robin Holliday’s precedent1 in using the term more broadly- in this case to refer to regulation of gene expression and other downstream effects caused by hormones). Epigenetics “The construction of a building is as important as the blueprint.” -Our Stolen Future, page 204 Hormones (such as the androgen testosterone) are like footballs; hormone-producing glands such as the adrenal gland are like the quarterbacks that throw the footballs; and wide receivers are the hormone receptors- proteins embedded in cell membranes or cytoplasm which “catch” the football and pass its signal down into the cell. After being caught, the hormone football then degrades. The football’s signal exerts influence upon (epi) the genetic (genetic= hence, epigenetics) expression of the cell. The most typical cellular responses to catching the football are to up- or downregulate gene expression: meaning that the number of proteins the cell translates from a particular gene goes either up or down. If there are too many or too few received footballs, disaster can occur (e.g. testes won’t develop). Okay, so we’ve got the basics of the endocrine system- what next? Without the activity of the endocrine system, especially of androgens, an embryo cannot become phenotypically male. For instance, for a short time embryos have a pair of partially developed organs that if left to themselves will turn into ovaries. If acted on by “downstream” elements from TDF, however, the gonads will become testes. Similarly, many typically male phenotypes are dependent, not only on genes, but upon precise dosages and timing of specific hormones. Though the causes of fetal hormone variance are not substantially understood, their role in sex determination is. For emphasis, I’ll repeat the bottom line: sex determination is not merely genetic; it relies necessarily on the endocrine system. Now for why this matters. I noted above that Colborn’s book argued that some industrial chemicals are affecting human fertility and sex determination. The reason? The industrial chemicals do what some plants have been doing for millennia: they manipulate the human endocrine system to decrease human fertility (the evolutionist might argue that so doing results in less predation of the plant over time). The most common ways chemicals disrupt the endocrine system:     They block the ball (for instance, by binding to or disfiguring the hormones) They hold the receiver (by binding to the receivers’ hands so there’s no room for hormones) They throw their own football-like balls into the air (known as hormone mimics) They tackle the quarterback (block the glands from producing or releasing hormones)

These endocrine disrupting effects often take place entirely independent of genes or gene expression. Because some wide receivers will catch about anything that’s lofted to them, the mimics oftentimes don’t even need to bear a resemblance to an actual football- even a lampshade sometimes does the trick. To complicate matters, hormone mimics and defensive linemen tend to stick around, rather than degrading like good little footballs do after they’re caught- thus, they can go through the cycle again and again.
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Holliday, R., 1990. Mechanisms for the control of gene activity during development. Biol. Rev. Cambr. Philos. Soc. 65, 431-471.

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The same effects caused by endocrine disrupters can occur if genes coding for hormone receptors are flawed, or if glands don’t produce hormones in the right conformations (shapes) and amounts and at the right times. What kinds of effects do we see in the animal kingdom (including Homo sapiens) when these internally and externally induced Step 2 problems occur?  In the early 70’s, for the first recorded time male-female nesting pairs of western gulls were replaced by same-sex female pairs with extraordinarily large numbers of eggs. The eggshells were thinner than usual, and the next two decades witnessed the spread of this phenomenon from Southern California to the Great Lakes, Puget Sound, and the coast of Massachusetts2 CAIS (Complete Androgen Insensitivity Syndrome) – human beings that are phenotypically female but genetically male. These individuals have gonads inside, but they’re testes instead of ovaries. The genetic maleness of these people usually isn’t noticed until puberty when menstruation fails to start. PAIS (Partial Androgen Insensitivity Syndrome)- the phallic structure varies in every degree between a penis and a clitoris. The genotype is male (XY). Some have a single orifice connected to both the urethra and the vagina. These people span the entire range from predominantly phenotypically female to predominantly phenotypically male. During the 80’s, alligators in the Florida lakes decreased hatching percent from 90% to 18%, and half of the baby gators died within 10 days. Though there was a pesticide spill in their lake in 1980, the effects weren’t witnessed until years later. This is an example of the transgenerational effects of some endocrine disruptors- meaning that you don’t see problems until the fetuses that got the wrong dose at the right time or the right dose at the wrong time reach sexual maturity and have trouble reproducing a generation later3 A review of 61 studies revealed that from 1938 to 1980, human sperm abnormalities are up, sperm counts are down, testicular cancer is up, the incidence of undescended testicles is up, and the incidence of shortened testicles is up4 The sons of female rats given a small dose of dioxin (a hormone mimic) on the fifteenth day of pregnancy, a crucial window in sex determination, had sperm reductions as high as 56% less than their peers whose mom’s hadn’t been given the dioxin (interestingly, rats have ridiculously more sperm than they need, so even a hit of 56% won’t likely affect their fertility. Humans, on the other hand, have just barely enough). Additionally, the sons whose moms were poisoned were much less likely to sexually act like males and much more likely to arch their backs in the typically female response known as lordosis, and allow another male to mount them5

I could go on, but the other effects follow similar lines, i.e. they confirm that sexual differentiation and reproductive problems result from endocrine disruption. The timing and doses of hormones floating around in the womb during the critical sex determining phases of fetal development are like the small rudders which turn huge ships. Bottom line of this primer on sex determination? Both 1) genes and 2) the intra-organismal environment (i.e. the womb) play a huge role in sex determination.

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Theo Colborn, Our Stolen Future, chapter 1. Theo Colborn, Our Stolen Future, chapter 1. 4 Theo Colborn, Our Stolen Future, chapter 1. 5 Theo Colborn, Our Stolen Future, chapter 1.

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