Increased occurrence of reproductive disorders has raised concerns regarding the impact of endocrine-disrupting chemicals on reproductive health, especially when such exposure occurs during fetal life. Prenatal testosterone (T) treatment leads to growth retardation, postnatal hypergonadotropism, compromised estradiol-positive feedback, polycystic ovaries, and infertility in the adult. Prenatal dihydrotestosterone treatment failed to affect ovarian morphology or estradiol-positive feedback, suggesting that effects of prenatal T may be facilitated via conversion of T to estradiol, thus raising concerns regarding fetal exposure to estrogenic endocrine-disrupting chemicals. This study tested whether fetal exposure to methoxychlor (MXC) or bisphenol A (BPA) would disrupt cyclicity in the ewe. Suffolk ewes were administered MXC (n=10), BPA (n=10) (5 mg/kg.d sc in cotton seed oil) or the vehicle (C; n=16) from d 30 to 90 of gestation. On d 60 of treatment, maternal MXC concentrations in fat tissue and BPA in blood averaged approximately 200 microg/g fat and 37.4+/-3.3 ng/ml, respectively. Birth weights of BPA offspring were lower (P<0.05) relative to C. There was no difference in the time of puberty between groups. BPA females were hypergonadotropic during early postnatal life and ended their breeding season later, compared with C. Characterization of cyclic changes after synchronization with prostaglandin F2alpha in five C, six MXC, and six BPA females found that the onset of the LH surge was delayed in MXC (P<0.05) and the LH surge magnitude severely dampened (P<0.05) in BPA sheep. These findings suggest that prenatal BPA and MXC exposure have long-term differential effects on a variety of reproductive endocrine parameters that could impact fertility.

There have been anecdotal reports of increases in birth defects and cancer in Fallujah, Iraq blamed on the use of novel weapons (possibly including depleted uranium) in heavy fighting which occurred in that town between US led forces and local elements in 2004. In Jan/Feb 2010 the authors organised a team of researchers who visited 711 houses in Fallujah, Iraq and obtained responses to a questionnaire in Arabic on cancer, birth defects and infant mortality. The total population in the resulting sample was 4,843 persons with and overall response rate was better than 60%. Relative Risks for cancer were age-standardised and compared to rates in the Middle East Cancer Registry (MECC, Garbiah Egypt) for 1999 and rates in Jordan 1996–2001. Between Jan 2005 and the survey end date there were 62 cases of cancer malignancy reported (RR = 4.22; CI: 2.8, 6.6; p < 0.00000001) including 16 cases of childhood cancer 0–14 (RR = 12.6; CI: 4.9, 32; p < 0.00000001). Highest risks were found in all-leukaemia in the age groups 0–34 (20 cases RR = 38.5; CI: 19.2, 77; p < 0.00000001), all lymphoma 0–34 (8 cases, RR = 9.24;CI: 4.12, 20.8; p < 0.00000001), female breast cancer 0–44 (12 cases RR = 9.7;CI: 3.6, 25.6; p < 0.00000001) and brain tumours all ages (4 cases, RR = 7.4;CI: 2.4, 23.1; P < 0.004). Infant mortality was based on the mean birth rate over the 4 year period 2006–2009 with 1/6th added for cases reported in January and February 2010. There were 34 deaths in the age group 0–1 in this period giving a rate of 80 deaths per 1,000 births. This may be compared with a rate of 19.8 in Egypt (RR = 4.2 p < 0.00001) 17 in Jordan in 2008 and 9.7 in Kuwait in 2008. The mean birth sex-ratio in the recent 5-year cohort was anomalous. Normally the sex ratio in human populations is a constant with 1,050 boys born to 1,000 girls. This is disturbed if there is a genetic damage stress. The ratio of boys to 1,000 girls in the 0–4, 5–9, 10–14 and 15–19 age cohorts in the Fallujah sample were 860, 1,182, 1,108 and 1,010 respectively suggesting genetic damage to the 0–4 group (p < 0.01). Whilst the results seem to qualitatively support the existence of serious mutation-related health effects in Fallujah, owing to the structural problems associated with surveys of this kind, care should be exercised in interpreting the findings quantitatively.

The inappropriate programming of developing organ systems by exposure to excess native or environmental steroids, particularly the contamination of our environment and our food sources with synthetic endocrine disrupting chemicals that can interact with steroid receptors, is a major concern. Studies with native steroids have found that in utero exposure of sheep to excess testosterone, an estrogen precursor, results in low birth weight offspring and leads to an array of adult reproductive / metabolic deficits manifested as cycle defects, functional hyperandrogenism, neuroendocrine / ovarian defects, insulin resistance, and hypertension. Furthermore, the severity of reproductive dysfunction is amplified by excess postnatal weight gain. The constellation of adult reproductive and metabolic dysfunction in prenatal testosterone-treated sheep is similar to features seen in women with polycystic ovary syndrome. Prenatal dihydrotestosterone treatment failed to result in similar phenotype suggesting that many effects of prenatal testosterone excess are likely facilitated via aromatization to estradiol. Similarly, exposure to environmental steroid imposters such as bisphenol A (BPA) and methoxychlor (MXC) from days 30-90 of gestation had long-term but differential effects. Exposure of sheep to BPA, which resulted in maternal levels of 30-50 ng/ml BPA, culminated in low birth-weight offspring. These female offspring were hypergonadotropic during early postnatal life and characterized by severely dampened preovulatory LH surges. Prenatal MXC-treated females had normal birth weight and manifested delayed but normal amplitude LH surges. Importantly, the effects of BPA were evident at levels, which approximated twice the highest levels found in human maternal circulation of industrialized nations. These findings provide evidence in support of developmental origin of adult reproductive and metabolic diseases and highlight the risk posed by exposure to environmental endocrine disrupting chemicals.

Between October 1994 and October 1995, the number of birth defects per 1,000 live births in Al Basrah Maternity Hospital was 1.37. In 2003, the number of birth defects in Al Basrah Maternity Hospital was 23 per 1,000 live births. Within less than a decade, the occurrence of congenital birth defects increased by an astonishing 17-fold in the same hospital. A yearly account of the occurrence and types of birth defects, between 2003 and 2011, in Al Basrah Maternity Hospital, was reported. Metal levels in hair, toenail, and tooth samples of residents of Al Basrah were also provided. The enamel portion of the deciduous tooth from a child with birth defects from Al Basrah (4.19 μg/g) had nearly three times higher lead than the whole teeth of children living in unimpacted areas. Lead was 1.4 times higher in the tooth enamel of parents of children with birth defects (2,497 ± 1,400 μg/g, mean ± SD) compared to parents of normal children (1,826 ± 1,819 μg/g). Our data suggested that birth defects in the Iraqi cities of Al Basrah (in the south of Iraq) and Fallujah (in central Iraq) are mainly folate-dependent. This knowledge offers possible treatment options and remediation plans for at-risk Iraqi populations.

Since 2003, congenital malformations have increased to account for 15% of all births in Fallujah, Iraq. Congenital heart defects have the highest incidence, followed by neural tube defects. Similar birth defects were reported in other populations exposed to war contaminants. While the causes of increased prevalence of birth defects are under investigation, we opted to release this communication to contribute to exploration of these issues. By using a questionnaire, containing residential history and activities that may have led to exposure to war contaminants, retrospective reproductive history of four polygamous Fallujah families were documented. Our findings point to sporadic, untargeted events, with different phenotypes in each family and increased recurrence. The prevalence of familial birth defects after 2003 highlights the relevance of epigenetic mechanisms and offers insights to focus research, with the aim of reducing further damage to people's health.

Feather and muscle of 10 avian species (n = 46), were analyzed for polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs). Muscle contained significantly higher PCB and OCP than liver and feather. Mean muscle and feather PCB was 408.5 ± 134.5 and 32 ± 4.5 ng/g wet weight. Highly chlorinated PCBs were found in muscle and liver while feather had PCBs with less chlorination. Gulls had highest levels of both pollutants. Gull feather PCB and OCP were strongly correlated with their levels in the liver and muscle tissues (0.6 < r < 0.9, p < 0.01). Analysis of gull feather can be used as a non-invasive method for monitoring organic pollutants.

Prenatal exposure of the female sheep to excess testosterone (T) leads to hypergonadotropism, multifollicular ovaries, and progressive loss of reproductive cycles. We have determined that prenatal T treatment delays the latency of the estradiol (E2)-induced LH surge. To extend this finding into a natural physiological context, the present study was conducted to determine if the malprogrammed surge mechanism alters the reproductive cycle. Specifically, we wished to determine if prenatal T treatment 1) delays the onset of the preovulatory gonadotropin surge during the natural follicular phase rise in E2, 2) alters pulsatile LH secretion and the dynamics of the secondary FSH surge, and 3) compromises the ensuing luteal function. Females prenatally T-treated from Day 60 to Day 90 of gestation (147 days is term) and control females were studied when they were approximately 2.5 yr of age. Reproductive cycles of control and prenatally T-treated females were synchronized with PGF2alpha, and peripheral blood samples were collected every 2 h for 120 h to characterize cyclic changes in E2, LH, and FSH and then daily for 14 days to monitor changes in luteal progesterone. To assess LH pulse patterns, blood samples were also collected frequently (each 5 min for 6 h) during the follicular and luteal phases of the cycle. The results revealed that, in prenatally T-treated females, 1) the preovulatory increase in E2 was normal; 2) the latencies between the preovulatory increase in E2 and the peaks of the primary LH and FSH surges were longer, but the magnitudes similar; 3) follicular-phase LH pulse frequency was increased; 4) the interval between the primary and secondary FSH surges was reduced but there was a tendency for an increase in duration of the secondary FSH surge; but 5) luteal progesterone patterns were in general unaltered. Thus, exposure of the female to excess T before birth produces perturbances and maltiming in periovulatory gonadotropin secretory dynamics, but these do not produce apparent defects in cycle regularity or luteal function. To reveal the pathologies that lead to the eventual subfertility arising from excess T exposure during midgestation, studies at older ages must be conducted to assess if there is progressive disruption of neuroendocrine and ovarian function.

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