The Galton Laboratory, University College London, Wolfson House, 4 Stephenson Way, London NW1 2HE, UK
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Abstract |
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Key words: estrogen/sex ratios/testosterone
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Introduction |
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The associations of offspring sex ratio with cycle day of insemination, coital rate, duration of gestation, side of ovulation, diet and parasitic infection |
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Cycle day of insemination
I cited evidence that time of insemination within the cycle is directly associated with sex of offspring not only in the human but also in white-tailed deer, Barbary macaque, golden hamster and the Norway rat (James, 1996). To this list, one may add the mouse (Jimenez et al., 2003
). Moreover, the evidence from human data has been strengthened by a meta-analysis on 10 independent data sets (James, 2000a
). The resultant MantelHaenszel test statistic was significant at the 0.005 level. So it is rather well established that the probability of a human male conception is higher in those occurring early and late in the fertile interval; and that the probability of a female is higher in the middle of that interval. These data are as would be predicted on the basis of the hypothesis; this is because of the gonadotrophin surge in the middle of the fertile interval (gonadotrophin concentrations are ex hypothesi positively associated with female births).
I cited evidence that in some polytocous species (rabbits, mice and pigs), the zygotes within a litter are formed across a period of time (James, 1996). So since the relevant maternal hormone concentrations vary across this time in polytocous species too, ex hypothesi the probability P (that a zygote will be male) will vary across the zygotes within a litter. If that were so, it would constitute an example of Poisson variation. Also it is a standard result in probability theory that Poisson variation is associated with a variance that is less than that of the binomial with the same mean (Edwards, 1960
). I cited evidence for such sub-binomial variance in pigs, rabbits, mice, sheep, golden hamsters and rats (James, 1996
). I suggest that this indirect evidence supports the notion that in these polytocous species, P (the probability of a male zygote) varies with time across the fertile interval (just as is suggested above by direct data in respect of the human).
Coital rate
It has been shown mathematically that if the offspring sex ratio (proportion male) were dependent on time of insemination, then the sex ratio would also be (weakly) associated with coital rate (Roberts, 1978). I cited data suggesting that high coital rates are associated with male offspring in horses, rabbits, rats, mice and apparently seals (James, 1996
). That paper also adduces indirect data suggesting such a relationship in the human; moreover, (admittedly weak) direct data have also been published on the point (James, 1995a
). All these data are consistent with the present hypothesis; indeed they would be predicted from it.
Duration of gestation
The association between sex ratio and duration of gestation is a continuing source of concern. Prematurity is associated with substantial morbidity and mortality, and its cause is not established. However, there is an excess of males among premature babies. So it has been suggested that the causes of initiation of labour lie in the sex of the fetus. However, what is not usually noticed in this context is that the regression of the sex ratio on duration of gestation is reverse-J-shaped. In other words, there are excess males not only among premature babies, but also among postmature ones. Indeed, my explanation (James, 1994a) seems the only one capable of accounting for this reverse-J. This is that the established U-shaped regression of sex ratio on cycle day of insemination is responsible for a similar much-damped regression 9 months later, i.e. of sex ratio on duration of gestation. Efforts to strengthen this argument appear in James (2002a
, 2003). It is also strengthened by the finding of excess males among postmature babies in a large sample of accurately dated births (Divon et al., 2002
).
Side of ovulation
Schoner (1927) reported that boys are more likely to follow right-sided ovulation than left-sided ovulation. Fukuda et al. (2000
) reported that serum estradiol and testosterone concentrations are higher in right-sided than left-sided ovulation. I suggest the one is due to the other.
Diet
Rosenfeld et al. (2003) reported that female mice fed a high-fat diet produce litters that are predominantly male-biased, and that those fed a low-fat diet produce litters that are predominantly female-biased. Taking litters (male-biased or not) as the unit of observation,
2 = 38.2, P < 0.00001. I know of no data relating steroid hormones to fat in the diet of mice, but in adolescent girls, modest reductions in fat intake are associated with changes in steroid hormone concentrations including reductions in levels of estrogens (Dorgan et al., 2003
). So it seems likely that (as suspected by Rosenfeld et al., 2003
) the dietary effect on sex ratios was hormonally mediated. Curiously enough, Moles et al. (2003
) reported that the number of male pups being carried by a pregnant female mouse was negatively associated with a maternal preference for a high-fat diet. These authors also found that the number of male fetuses on pregnancy day 18 correlated positively with maternal testosterone, and they observed that one explanation of their findings was that baseline maternal testosterone may influence both the sex ratio and female taste preferences.
Parasitic infection
Ehman and Scott (2002) found that litters sired by male mice parasitized by Heligmosomoides polygyrus had significantly low sex ratios. Parasitic infection of male mammals (including mice) lowers their testosterone levels (Hillgarth and Wingfield, 1997
; Barnard et al., 1998
). So Ehman and Scott (2002
) suggested that parasite-induced hormonal changes may alter the sex ratio of offspring.
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Illness |
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Testicular cancer
Men destined to suffer (and those who have been diagnosed with) this cancer reportedly sire significant excesses of daughters (Moller, 1998; Jacobsen et al., 2000
; though see Richiardi et al., 2004
). Consistent with the hypothesis, these men are also reported to have low testosterone/gonadotrophin ratios (Petersen et al., 1999
)
Multiple sclerosis
After disease onset (but not before), men with multiple sclerosis (MS) reportedly sire a significant excess of daughters, and women with MS bear a (non-significant) excess of sons (James, 1994b, 2002b). Both these results may be construed to be consistent with the hypothesis because MS patients reportedly have enlarged adrenals (Reder et al., 1994
). The reasonable inference is that the condition causes stress; and stress is associated with low testosterone concentrations in men and high (adrenal) androgens in women (Kemper, 1990
).
Pathological obstetric conditions
Unusual offspring sex ratios are associated with a number of obstetric conditions. Highly significant male excesses have been reported in placenta praevia, fatty liver of pregnancy and (some forms of) toxaemia (James, 1995b) and dermatoses of pregnancy (James, 2000b
); and highly significant female excesses in placenta accreta and extrauterine pregnancy (James, 1995b
) and hyperemesis gravidarum (James, 2001a
). Fetal sex is not thought to be the cause of any of these conditions, and I suggested that the abnormal sex ratios are caused by unusual maternal hormone profiles around the time of conception; and that these same abnormal hormone profiles persist, and later are partially responsible for the pathology (James, 1995b
). The suggestion was speculative at the time, but has gained strength with regard to placenta praevia and extrauterine pregnancy (James, 2001b
), pre-eclampsia (James, 2002c
), dermatoses of pregnancy (James, 2000b
) and perhaps acute fatty liver of pregnancy (James, 2002d
)
Viral diseases
Two forms of viral disease have been associated with unusual offspring sex ratios. Hepatitis B (HBV) carriers (of both sexes) have repeatedly been shown to have significant excesses of sons (Chahnazarian et al., 1988); and women who are seropositive for cytomegalovirus (CMV) bear a significant excess of daughters (Piazze et al., 1999
; Shields et al., 2002
). I suggest that the explanations are as follows. Estrogen has a generally suppressive effect on CMV replication (Speir et al., 2000
). Therefore, estrogen concentrations may be assumed to be low in CMV-seropositive women; hence, ex hypothesi, the low offspring sex ratio of CMV-positive women. Moreover, testosterone concentrations are reported to be positively associated with hepatitis B surface antigen levels in men (Jilma et al., 1998
); hence, ex hypothesi, the high offspring sex ratio of offspring of carriers. The present line of reasoning is supported by the (otherwise unexplained) highly significant excess of brothers among the sibs of hepatitis B carriers (Mazzur and Watson, 1974
). Testosterone concentrations have strong genetic determinants (Meikle et al., 1997
; Harris et al., 1998
).
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Chemical exposures |
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When the sexes of the exposed parents are controlled, paternal exposures to a number of chemicals used in war and agriculture (herbicides, pesticides, fungicides, etc.) reportedly reduce the sex ratios of subsequently born children. In some such studies, men have been exposed to a cocktail of chemicals. In the ideal study, there should be data on the exact chemical agents, on the endocrine profiles of the exposed workers, and on the sexes of offspring of the exposed workers. However, as far as I know, such data are available in only one set of studies. Garry et al. (2002a,b) reported significant excesses of daughters born to the wives of fungicide applicators. These workers also described a significant negative correlation between the mens testosterone concentrations and their number of daughters (Garry et al., 2003
). These authors concluded that fungicides seem to determine the sex of offspring. I suggest that this is correct, and that they do so by lowering the testosterone levels of exposed men. In the following section, the sex ratios associated with exposure to some chemical compounds are treated individually.
Dioxins and dioxin-like vompounds
I should declare an interest here. On the basis of my hypothesis and the finding of a low testosterone/gonadotrophin ratio in exposed men (Egeland et al., 1994), I predicted that exposed men would sire an excess of daughters (James, 1995c
). At first, the results of Mocarelli et al. (2000
) seemed to confirm the prediction but, since then, other data have become available. Some confirm this result (Moshammer and Neuberger, 2000
; Ryan et al., 2002
; del Rio Gomez et al., 2002
); however, others did not, reporting significantly raised offspring sex ratios of exposed men (Schnorr et al., 2001
; Karmaus et al., 2002
). The discrepancies among these results may be the consequence of different degrees of contamination with congeners (James, 2002e
). Some congeners have estrogenic properties, and some anti-estrogenic or androgenic properties (Karmaus et al., 2002
) which, ex hypothesi, would affect offspring sex ratios. What is clear is that paternal exposure to some dioxin-like compounds affects the offspring sex ratio in one direction or the other (mediated ex hypothesi by hormones).
Dibromochloropropane (DBCP)
Paternal exposure to DBCP is associated with a significantly lowered subsequent offspring sex ratio (Potashnik and Yanai-Inbar, 1987). These authors conducted more than one study on the topic, and their later work confirmed this result. Consistent with my hypothesis, Whorton et al. (1979
) reported a low testosterone/gonadotrophin ratio in exposed men. DBCP has since been banned from most countries and, as far as I know, no further studies have been published on its effects on human offspring sex ratios.
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Paternal occupational exposures |
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Professional driving
Noting the evidence that professional drivers have poor sperm quality, and the evidence that lead lowers male testosterone levels, I speculated thatif my hypothesis were correctthen professional drivers should sire an excess of daughters (James, 1992). Dickinson and Parker (1994
) confirmed this prediction on two large samples, namely those on births in England and Wales 19801982 and their own data on Cumbrian births 19501989. Taken jointly, the data confirm my prediction at the 0.02 level.
Professional diving
Rockert (1977) reported 20 sons and 40 daughters born to deep divers in the Swedish Navy. Lyster (1982
) reported 45 sons and 85 daughters born to Australian abalone divers. These two sex ratios were significantly lower than the contemporaneous comparable national live birth sex ratios P = 0.005 and P < 0.002, respectively). Rockert et al. (1978
) reported that the testosterone levels of rats exposed to a hyperbaric environment of air were significantly and substantially (
50%) reduced. Rockert and Haglid (1983
) reported that preliminary results from determination of plasma testosterone in human divers show a decrease after diving. Ex hypothesi, the low sex ratios of the offspring of divers is due to low testosterone levels in these men. Indeed, the continuing warnings of the dangers of professional and recreational diving (Sharp, 2003
) suggest that the hormone concentrations of divers (recreational and professional) should be assayed further.
Pilots of high-performance aircraft and spacecraft
Low offspring sex ratios have been reported in respect of pilots of high-performance aircraft and spacecraft (Snyder, 1961; Goerres and Gerbert, 1976
; Little et al., 1987
). Low testosterone/gonadotrophin ratios in such men and in experimental animals have been reported by Ortiz et al. (2000
), Strollo et al. (1998
) and Strollo (1999
). I suggest that the low sex ratios are consequent on the low testosterone/gonadotrophin ratios.
Non-ionizing radiation
I noted that men exposed to non-ionizing radiation reportedly subsequently sired excesses of daughters (James, 1997b). I suggested that such men may have a hormone profile of non-specific pathology. So it is gratifying that Grajewski et al. (2000
) have confirmed this prediction in reporting a significantly low testosterone level in radiofrequency heater operators.
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Teratology |
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Genetics |
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A curious feature of animal breeding studies is that attempts to breed for one trait have sometimes led to unexpected and unexplained correlated changes in offspring sex ratio. For instance, Weir (1955) demonstrated this when selectively breeding for pH in mice; and similar results have been reported following selective breeding for high and low levels of sexual drive in rats (Rasmussen, 1950; cited by Bernstein and Martinez-Gustin, 1961
); high and low resistance to a dietary toxin in mice (Hohenboken et al., 1998
); high body weight in mice (Wilson et al., 1971
); and high and low adult sex dimorphism in body weight in mice (Krackow et al., 2003
). Divergent selection of mice for body weight results in incidental selection for testosterone, thyroid hormone and growth hormone concentrations (Hastings and Hill, 1997
; Bunger et al., 1998
). Thus my hypothesis has the potential of explaining all this otherwise unexplained correlated variation in offspring sex ratio (James, 2004b
).
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Predictions |
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The influence on offspring sex ratio of rodent dams own adjacent littermates in utero
It was evident that the intrauterine position of rodents is associated with their subsequent adult hormone levels; females adjacent in utero to two males (2M females) are more androgenized than females adjacent to two females (0M females). This is due to the transference of testosterone from male fetuses to adjacent female ones (Ryan and Vandenbergh, 2002). So I predicted that the sex ratio of the offspring of 0M females would differ from that of 2M females (James, 1989
). The point has since been confirmed in female gerbils (Clark et al ., 1993
; Clark and Galef, 1994
) and mice (Vandenbergh and Huggett, 1994
). I know of no other explanation for this phenomenon.
Finger length ratios, splenial areas and offspring sex ratios
Substantial quantities of data have been adduced to support the hypothesis that R, the ratio of the lengths of the second (2D) and fourth (4D) fingers (where R = 2D/4D) is negatively correlated with mens testosterone concentrations (e.g. Manning, 2002). Accordingly, I predicted that mens R values should correlate negatively with their offspring sex ratios (James, 2001c
). (It is worth noting that my prediction in no sense depends on whether Mannings phenomenon is of prenatal or postnatal origin.) My prediction was confirmed by Manning et al. (2002
).
It is worth commenting on a reportedly analogous phenomenon in the rat. In this species, the splenium of the corpus callosum is sexually dimorphic, being larger in males. Testosterone injections in females increase the size of their splenium. In accordance with my hypothesis, Nunez and Juraska (1998) found that the offspring sex ratio of females correlates with their splenial area.
HLA genes, hormones and human offspring sex ratios
I suggested that some HLA genes operate as markers for disease by indexing hormone levels which are pathogenic (James, 1991). Ollier et al. (1989
) had assayed the testosterone levels of 71 men with definite rheumatoid arthritis and 138 healthy controls. These men were categorized by the presence or absence of eight HLA A genes and 12 HLA B genes. In both patients and controls, the men who were HLA B15 positive had the lowest mean testosterone levels. Accordingly, Astolfi et al. (2001
) tested a prediction based on my hypothesis, namely that men carrying HLA B15 should sire a high proportion of daughters. The prediction was confirmed and these authors wrote These results suggest an effect of HLA B15 on the secondary sex ratio mediated by a low testosterone level.
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Comment on other sex ratio hypotheses |
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Under these circumstances, females would have more grandchildren if mothers in good condition were to have disproportionately more sons; and those in poor condition had disproportionately more daughters. These authors hypothesized that under these conditions, such skewed offspring sex ratios actually exist. The hypothesis has occasioned much subsequent research in which workers frequently have used maternal dominance rank as a surrogate for maternal condition. The TW hypothesis has been strikingly successful in regard to non-primate species. However, this is not so in regard to non-human primates (Brown and Silk, 2002) and humans (Lazarus, 2002
). Though there have been nearly 100 studies on the point, these have included as many failures to confirm as confirmations of the hypothesis. I suggest that this is not because the TW hypothesis is false, but because the relevant hormones (testosterone and estrogen) also affect health, personality, attractiveness and behaviour. For instance, they differentially affect our immune systems and act as neurotransmitters (Seeman, 1996
), and so partially control our moods, and mental and neurological diseases (e.g. chronic depression, schizophrenia, and Parkinsons and Alzheimers diseases). Testosterone levels are in causal loops with our behaviour, e.g. both causing and responding to our successes and failures in games (Neave and Wolfson, 2003
). Gonadal hormones are causally associated with personality traits and emotions, e.g. aggression (Harris et al., 1996
); extraversion (King et al 1995
); fear, tenacity and emotional bonding (Ellis, 1986
; Burnham et al., 2003
); sensation seeking (Zuckerman, 1994
); and sexual drive and performance in males (Mantzoros et al., 1995
) and females (Morris et al., 1987
). In short, myriad circumstances may cause constraints on the working of adaptive mechanisms in sex ratio. If I am right, the proximate causes of sex ratio variation will have to be established before a conclusive judgement may be offered on TW.
Other hypotheses
A number of workers have suggested that the ultimate source of human sex ratio variation is one of the above-mentioned variables, e.g. genetics (Bernstein, 1954); coital rate (Wells, 1990
); timing of insemination (Whelan, 1977
) and a hormonally associated trait, maternal dominance ranking (Grant, 1998
). A detailed discussion of each of these hypotheses would be inappropriate here. However, my perception is that each of these hypotheses resembles one of the mythical accounts of blind people being asked to describe an elephant; each has grasped at a truth, but not the whole truth. I would contend that each of these hypotheses is deducible from mine, and is true for that reason.
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Acknowledgements |
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References |
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Submitted on October 8, 2003; accepted on March 15, 2004.